CN1131911A - Anthracyclinone derivatives and their use in amyloidosis - Google Patents

Anthracyclinone derivatives and their use in amyloidosis Download PDF

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CN1131911A
CN1131911A CN95190743A CN95190743A CN1131911A CN 1131911 A CN1131911 A CN 1131911A CN 95190743 A CN95190743 A CN 95190743A CN 95190743 A CN95190743 A CN 95190743A CN 1131911 A CN1131911 A CN 1131911A
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CN1200699C (en
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A·萨拉托
J·兰森
M·卡鲁索
D·巴林阿里
T·班迪拉
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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Abstract

The present invention provides the new use in the treatment of amyloidosis with the anthracyclinone of formula (A) wherein R1, R2, R3, R4, and R5, are appropriate substituents. Some compounds of formula (A) are novel. Processes for their preparation and pharmaceutical composition containing them are also described.

Description

Anthracyclinone derivatives and the purposes in amyloidosis thereof
The present invention relates to the treatment of amyloidosis, relate to the new compound that is used for this treatment, relate to its preparation method and contain their pharmaceutical composition.
As if the relation between the forfeiture of amyloidosis, cell death and function of organization relevant with dissimilar diseases (comprising nerve degeneration).Therefore, prevent that amyloid from forming and/or inducing amyloid to decompose may be a kind of critical treatment means of all pathology relevant with the amyloidosis that comprises AL amyloidosis imbalances and Alzheimer type nerve degeneration disease.
More particularly, the invention provides the anthrone (anthracyclinone) of formula A and pharmaceutically acceptable salt thereof and be used for the treatment of purposes in the medicine of amyloidosis in preparation:
Figure A9519074300171
R wherein 1Expression:
-hydrogen or hydroxyl;
-Shi OR 6Group, R wherein 6Be C 1-C 6Alkyl, C 5-C 6Cycloalkyl or CH 2Ph, phenyl ring (Ph) randomly is selected from F, Cl, Br, C by 1,2 or 3 1-C 6Alkyl, C 1-C 6Alkoxyl and CF 3Substituent group replace;
Or
-Shi OSO 2R 7Group, R wherein 7Be C 1-C 6Alkyl or randomly be selected from halogen such as F, Cl or Br and C by 1,2 or 3 1-C 6The ph that the substituent group of alkyl replaces;
R 2Expression hydrogen, hydroxyl, OR 6, COOH or COOR 6, R wherein 6As defined above;
R 3Expression hydrogen, hydroxyl or OR as defined above 6
R 4Expression hydrogen, methyl or formula XCH 2R 8Group, wherein X is CO, CH 2, group shown in CHOH or the following formula:
Figure A9519074300181
Wherein m is 2 or 3, and R 8For
-hydrogen or hydroxyl;
-Shi NR 9R 10Group, wherein:
-R 9And R 10Be selected from independently of one another:
(a) hydrogen,
(b) randomly by hydroxyl, CN, COR 11, COOR 11, CONR 11R 12, O (CH 2) nNR 11R 12(n is 2-4) or NR 11R 12The C that replaces 1-C 6Alkyl or C 2-C 6Alkenyl, wherein R 11And R 12Be selected from hydrogen, C independently of one another 1-C 12Alkyl or C 2-C 12Alkenyl or randomly be selected from C by one or more (for example 1,2 or 3) 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the phenyl of the substituent group of CN replacement,
(C) randomly by COR 11, COOR 11Or the C of OH replacement 3-C 6Cycloalkyl, wherein R 11As defined above
(d) randomly on phenyl ring, be selected from C by one or more (for example 1,2 or 3) 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the phenyl (C of the substituent group of CN replacement 1-C 4Alkyl or C 2-C 4Alkenyl), or
(e) COR 11, COOR 11, CONR 11R 12, COCH 2NR 11R 12, CONR 11COOR 12Or SO 2R 12, R wherein 11And R 12As defined above, or
-R 9And R 10Form with the nitrogen-atoms that links to each other with them:
(f) randomly by C 1-C 4Alkyl or C 1-C 4The morpholine ring that alkoxyl replaces,
(g) randomly by C 1-C 6Alkyl, C 2-C 6Alkenyl or optional be selected from C by one or more (for example 1,2 or 3) 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the piperazine ring of the phenyl replacement of the substituent group of CN replacement, or
(h) randomly by OH, NH 2, COOH, COOR 11Or CONR 11R 12(R wherein 11And R 12C as defined above), 1-C 6Alkyl, C 2-C 6Alkenyl or randomly be selected from C by one or more (for example 1,2 or 3) 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH2 or CN the phenyl that replaces of the substituent group pyrrolidine ring or piperidine ring or the tetrahydro pyridine ring that replace;
-Shi OR 6Or SR 6Group, R wherein 6As defined above;
The group of-Shi O-Ph, wherein benzene (Ph) ring is randomly by nitro, amino or NR as defined above 9R 10Replace;
Group shown in the-Shi B:
R wherein 13Expression hydrogen, COR 11(R wherein 11As defined above) or peptide residue, R 14Be halogen or formula OSO 2R 7(R wherein 7Group as defined above); Or
Group shown in-Shi C or the D:
Wherein E is formula COOR 11Or CONR 9R 10(R wherein 9, R 10And R 11Group as defined above); With
R 5Expression hydrogen, hydroxyl, formula OR 6Or NR 9R 10(R wherein 6, R 9And R 10Group as defined above), or the group shown in the formula F:
R wherein 6, R 9And R 10As defined above, p is 1-6.
The present invention provides the novel anthrone of above-mentioned formula A on the other hand, and condition is as follows:
-work as R 1Be H, OH or OCH 3, R 2Be H, R 3Be OH and R 4Be formula XCH 2OH or XCH 3During group shown in (wherein X is as defined above), R 5Do not represent R 9And R 10As descending defined NR to (h) at (a) to (c) or (e) 9R 10
-work as R 1Be H, OH or OCH 3, R 2Be H, OH, COOCH 3And R 4Be formula XCH 3Or XCH 2During group shown in the OH (wherein X is as defined above), R 5Can not be H or OH;
-work as R 1Be H or OH, R 5And R 4Be OH, and R 2During for H, R 4Can not be R ' wherein 6Be phenyl, benzyl, C 1-C 6Alkyl or C 5-C 6The COCH of cycloalkyl 2OR ' 6
The chemical compound of-Shi A is not one of following derivant:
14-(N-morpholino) daunomycinone
14-(N-piperidino) daunomycinone
14-acetylamino daunomycinone
14-acetylaminohydroxyphenylarsonic acid 4-demethoxylation daunomycinone
14-(N-morpholino) fuchsin ketone
14-(N-methyl-N-piperazine-1-yl) daunomycinone
14-(N-morpholino) fuchsin ketone
14-(N-methyl-N-piperazine) daunomycinone
Each alkyl, alkoxyl or alkenyl can be the straight or branched groups.
C 1-C 12Alkyl is C preferably 1-C 6Alkyl is more preferably C 1-C 4Alkyl.C 1-C 6Alkyl is C preferably 1-C 4Alkyl.C 1-C 6Alkyl is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl or n-pentyl preferably.C 1-C 6Alkyl is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group or sec-butyl preferably.
C 3-C 6Cycloalkyl is preferably C 5-C 6Cycloalkyl.C 5-C 6Cycloalkyl is cyclopenta or cyclohexyl preferably.
C 2-C 12Alkenyl is C preferably 2-C 6Alkenyl, more preferably C 2-C 4Alkenyl.C 2-C 6Alkenyl is C preferably 2-C 4Alkenyl.Preferred alkenyl is vinyl or acrylic.
Peptide residue can comprise 6 with interior (for example 1-4) amino acid residue.Suitable peptide residue is selected from Gly, Ala, Phe, Leu, Ghy-Phe, Leu-Gly, Val-Ala, Phe-Ala, Leu-Phe, Phe-Leu-Gly, Phe-Phe-Leu, Leu-Leu-Gly, Phe-Tyr-Ala, Phe-Gly-Phe, Phe-Leu-Gly-Phe, Gly-Phe-Leu-Gly, Gly-Phe-Leu-Gly.
R in the present invention 1Be preferably hydrogen or methoxyl group.R 2Select the excellent hydrogen that is.R 3Be preferably hydroxyl.R 4Be preferably formula XCH 2R 8Group, wherein X is CO, CH 2Or group shown in the following formula:
Figure A9519074300211
And R 8Be hydrogen, formula NR 9R 10Group, (wherein Ph ring randomly has NR to formula O-Ph 9R 10Replacement) group shown in, the group shown in formula B or the formula C, wherein R 9And R 10Be selected from independently of one another:
(a ') hydrogen,
(b ') is randomly by O (CH 2) nNR 11R 12Or NR 11R 12(wherein n, R 11And R 12The C of Qu Daiing as defined above) 1-C 4Alkyl,
(d ') randomly is selected from C by one or more (for example 1,2 or 3) on phenyl ring 1-C 4Alkyl, C 1-C 4Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the benzyl of the substituent group of CN replacement, or
(e ') COCF 3Or COCH 2NR 11R 12, wherein, R 11And R 12As defined above,
Or-R 9And R 10Form with the nitrogen-atoms that links to each other with them:
(f ') morpholine ring,
(g ') is randomly by C 1-C 4The piperazine ring that alkyl replaces, or
(h ' pyrrolidine ring or piperidine ring, or tetrahydro pyridine ring,
R in group shown in the formula B 3Be hydrogen, the R in group shown in the formula B 4Be I or OSO 2(C 1-C 4And the E in group shown in the formula C is formula CONR ' alkyl), 9R 10Shown group, wherein R ' 9And R ' 10Form randomly by C with the nitrogen-atoms that links to each other with them 1-C 4The piperazine ring that alkyl replaces.More preferably R 4Be group shown in the following formula:
Figure A9519074300221
Or formula XCH 2R 8Group, wherein X is CO or CH 2, R 8Be hydrogen, formula NR 9R 10Shown in group, group shown in the formula O-Ph, wherein Ph ring is randomly by NH 2Or NHCOCH 2N (C 1-C 4Alkyl) 2Replace group, wherein R shown in formula B or the formula C 9And R 10Be selected from independently of one another:
(a ") hydrogen,
(b ") is randomly by O (CH 2) nNH 2Or NH 2Methyl or ethyl that (wherein n is as defined above) replaces,
(d ") randomly is selected from C by 1,2 or 3 on phenyl ring 1-C 4Alkyl, C 1-C 4The benzyl that the substituent group of alkoxyl replaces, or
(e ") COCF 3Or COCH 2N (C 1-C 4Alkyl) 2,
Or-R 9And R 10Form with the nitrogen-atoms that links to each other with them:
(f ") morpholine ring,
(g ") is randomly by C 1-C 4The piperazine ring that alkyl replaces, or
(h ") pyrrolidine ring, piperidine ring, or 1,2,3,6-tetrahydro pyridine ring,
R in the group shown in the formula B 13Be hydrogen, R in the group shown in the formula B 14Be I or OSO 2(C 1-C 4Alkyl), and shown in the formula C in the group E be formula CONR ' 9R ' 10Shown in group, wherein R ' 9And R ' 10Form one randomly by C with the nitrogen-atoms that links to each other with them 1-C 4The piperazine ring that alkyl replaces.
R 5Be preferably hydrogen, hydroxyl or formula NR as defined above 9R 10Shown in group.
The invention provides the salt that those have the formula A chemical compound of salt forming group, especially have the salt of the chemical compound of carboxyl, basic group (for example amino); These salt mainly are physiologically acceptable salt, for example alkali metal salt and alkali salt (as sodium, potassium, lithium, calcium and magnesium salt), ammonium salt, with suitable organic amine or amino acids formed salt (as arginine, procaine salt and the adduct that forms by appropriate organic or mineral acid example hydrochloric acid, sulphuric acid, carboxylic acid and organic sulfonic acid (for example acetic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid).
The present invention comprises all possible stereoisomer or their raceme or optically active mixture.Preferred R 3Be in the α configuration, promptly be positioned under the plane of a loop.The instantiation that is used for preferred compound of the present invention is as follows: A1:14-(N-morpholino) daunomycinone A2:14-(N-piperidino) daunomycinone
Figure A9519074300242
A3:14-(N-pyrrolidine-1-yl) daunomycinone
Figure A9519074300243
A4:14-[N-(N '-methyl)-piperazine-1-yl] daunomycinone
Figure A9519074300244
A5:14-(3 ', 4 '-dimethoxy benzyl amino) daunomycinone R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2NHCH 2[C 6H 3(OCH 3) 2] A6:14-amino ethoxy ethylamino daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2NH (CH 2) 2O (CH 2) 2NH 2The amino ethylamino daunomycinone of A7:14-
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2NH (CH 2) 2NH 2A8:14-(N-aminoethyl-N-TFA amino) daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2N (COCF 3) (CH 2) 2NH 2A9:14-(N-amino ethoxy ethyl-N-TFA amino) daunomycinone
R 1=OCH 3, R 2=H, R 4=COCH 2N (COCF 3) (CH 2) 2O (CH 2) 2NH 2, R 3=R 5=OHA10:4-demethoxylation-14-(N-morpholino) daunomycinone
Figure A9519074300245
A12:4-demethoxylation-14-(N-pyrrolidinyl-1-yl) daunomycinone
Figure A9519074300251
A13:4-demethoxylation-14-N-[N '-methyl) piperazine-1-yl] daunomycinone
Figure A9519074300252
A14:4-demethoxylation-14-(3 ' 4 '-dimethoxy benzyl amino) daunomycinone R 1=R 2=H, R 3=R 5=OH, R 4=COCH 2NHCH 2[C 6H 3(OCH 3) 2] A15:4-demethoxylation-14-amino ethoxy ethylamino daunomycinone
R 1=R 2=H, R 3=R 5=OH, R 4=COCH 2NH (CH 2) 2O (CH 2) 2NH 2A16:4-demethoxylation-14-(N-amino ethoxy ethyl-N-TFA amino) daunomycinone
R 1=R 2=H, R 3=R 5=OH, R 4=COCH 2N (COCF 3) (CH 2) 2O (CH 2) 2NH 2
Figure A9519074300254
A20:7-deoxidation-14-[N-(N '-methyl)-piperazine-1-yl] daunomycinone
Figure A9519074300256
A21:7-deoxidation-14-(3 ' 4 '-dimethoxy benzyl amino) daunomycinone
R 1＝OCH 3，R 2＝R 5＝H，R 3＝OH，R 4＝COCH 2NHCH 2[C 6H 3(OCH 3) 2]
A22:7-deoxidation-14-amino ethoxy ethylamino daunomycinone
R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=COCH 2NH (CH 2) 2O (CH 2) 2NH 2A23:7-deoxidation-14-(N-amino ethoxy ethyl-N-TFA amino) daunomycinone
R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=COCH 2N (COCF 3) (CH 2) 2O (CH 2) 2NH 2A24:4-demethoxylation-7-dehydrogenation-14-(N-morpholino) daunomycinone
Figure A9519074300261
Figure A9519074300262
Figure A9519074300263
A27:4-demethoxylation-7-deoxidation-14-[N-(N-methyl) piperazine-1-yl] daunomycinone A28:4-demethoxylation-7-deoxidation-14-[3 '-(4 '-dimethyl oxygen base benzyl amino] daunomycinone
R 1=R 2=R 5=H, R 3=OH,, R 4=COCH 2NHCH 2[C 6H 3(OCH 3) 2] A29:4-demethoxylation-7-deoxidation-14-amino ethoxy ethylamino daunomycinone
R 1=R 2=R 5=H, R 3=OH, R 4=COCH 2NH (CH 2) 2O (CH 2) 2NH 2A30:7-deoxidation-7-(N-morpholino) daunomycinone
Figure A9519074300265
A31:7-deoxidation-7[pair (2 '-ethoxy)] amino daunomycinone
R 1=OCH 3, R 2=H, R 3=OH, R 4=COCH 3, R 5=N (CH 2CH 2OH) 2A32:7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino)-13-deoxidation generation-13-ethylenedioxy daunomycinone R 1=OCH 3, R 2=H, R 3=OH, R 4=C (OCH 2CH 2O) CH 3,
R 5=NHCH 2C 6H 3(OCH 3) 2A33:7-deoxidation-7-benzyl amino-13-deoxidation generation-13-ethylenedioxy daunomycinone
R 1=OCH 3, R 2=H, R 3=OH, R 4=C (OCH 2CH 2O) CH 3, R 5=NHCH 2C 6H 5A34:7-deoxidation-7-(2 '-hydroxyethylamino)-13-deoxidation generation-13-ethylenedioxy daunomycinone
R 1=OCH 3, R 2=H, R 3=OH, R 4=C (OCH 2CH 2O) CH 3, R 5=NHCH 2CH 2OHA35:4-demethoxylation-7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino)-13-deoxidation generation-13-ethylenedioxy daunomycinone
R 1=R 2=H, R 3=OH, R 4=C (OCH 2CH 2O) CH 3, R 5=NHCH 2C 6H 3(OCH 3) 2A36:7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino) daunomycinone
R 1=OCH 3, R 2=H, R 3=OH, R 4=COCH 3, R 5=NHCH 2C 6H 3(OCH 3) 2The amino daunomycinone of A37:7-deoxidation-7-benzyl
R 1=OCH 3, R 2=H, R 3=OH, R 4=COCH 3, R 5=NHCH 2C 6H 5A38:7-deoxidation-7-[(2 '-hydroxyethylamino)] daunomycinone
R 1=OCH 3, R 2=H, R 3=OH, R 4=COCH 3, R 5=NHCH 2CH 2OHA39:4-demethoxylation-7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino) daunomycinone
R 1=R 2=H, R 3=OH, R 4=COCH 3, R 5=NHCH 2C 6H 3(OCH 3) 2A40:7-deoxidation-7-amino-13-deoxidation generation-13-ethylenedioxy daunomycinone
R 1=OCH 3, R 2=H, R 3=OH, R 4=C (OCH 2CH 2O) CH 3, R 5=NH 2A41:4-demethoxylation-7-deoxidation-7-amino-13-deoxidation generation-13-ethylenedioxy daunomycinone
R 1=R 2=H, R 3=OH, R 4=C (OCH 2CH 2O) CH 3, R 5=NH 2The amino daunomycinone of A42:7-deoxidation-7-
R 1=OCH 3, R 2=H, R 3=OH, R 4=COCH 3, R 5=NH 2The amino daunomycinone R of A43:4-demethoxylation-7-deoxidation-7- 1=R 2=H, R 3=OH, R 4=COCH 3, R 5=NH 2
Figure A9519074300281
A46:1 3-deoxidation generation-14-amino ethoxy ethylamino daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=CH 2CH 2NH (CH 2) 2O (CH 2) 2NH 2A47:7-deoxidation-14-O-(3 '-amino-4 '-mesyl-2 ', 3 ', 4 ', 6 '-four deoxidations-L-pyrans lysol glycosyl) daunomycinone R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=COCH 2R 8
R wherein 8Be group (R shown in the formula B 13=H, R 14=OSO 2CH 3)
A48:7-deoxidation-14-O-(3 '-amino-4 '-sulphur generation-2 ', 3 ', 4 ', 6 '-four deoxidations-L-pyrans lysol glycosyl daunomycinone.R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=COCH 2R 8R wherein 8Be group (R shown in the formula B 13=H, R 14=I) A49:7-deoxidation-14-0-[2 '-(1 " piperazinyl) carbonyl Pentamethylene oxide .-6 '-yl] daunomycinone
Figure A9519074300282
A50:14-(p-aminophenyl oxygen base) daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2O-C 6H 4(pNH 2) A51:14-[is to (dimethylamino methyl carbonylamino) phenoxy group) daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2O-C 6H 4[pNHCOCH 2N (CH 3) 2] A52:4-demethoxylation-14-(p-aminophenyl oxygen base) daunomycinone
R 1=R 2=H, R 3=R 5=OH, R 4=COCH 2O-C 6H 4(p-NH 2) A53:4-demethoxylation-14-[is to (dimethylamino methyl carbonylamino) phenoxy group] daunomycinone
R 1=R 2=H, R 3=R 5=OH, R 4=COCH 2O-C 6H 4[p-NHCOCH 2N (CH 3) 2] A54:7-deoxidation-14-(p-aminophenyl oxygen base) daunomycinone
R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=COCH 2O-C 6H 4(p-NH 2) A55:7-deoxidation-14-[is to (dimethylamino methyl carbonylamino) phenoxy group] daunomycinone
R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=COCH 2O-C 6H 4[p-NHCOCH 2N (CH 3) 2] A56:7-deoxidation-4-demethoxylation-14-(p-aminophenyl oxygen base) daunomycinone
R 1=R 2=R 5=H, R 3=OH, R 4=COCH 2O-C 6H 4(p-NH 2) A57:7-deoxidation-4-demethoxylation-14-[is to (dimethylamino methyl carbonyl aminomethyl) phenoxy group] daunomycinone
R 1=R 2=R 5=H, R 3=OH, R 4=COCH 2O-C 6H 4[pNHCOCH 2N (CH 3) 2] A58:14-(N-lignocaine) daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 2N (C 2H 5) 2A59:13-dihydro-14-(N-morpholino) daunomycinone
R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=CHOHCH 2N (CH 2) 2OA60:7-deoxidation-13-dihydro-14-(N-morpholino) daunomycinone
R 1=OCH 3, R 2=R 5=H, R 3=OH, R 4=CHOHCH 2N (CH 2) 2OA61:4-demethoxylation-7-deoxidation-10-hydroxyl-14-(N-morpholino) daunomycinone
R 1=R 5=H, R 2=OH, R 4=COCH 2N (CH 2) 2OA62:4-demethoxylation-4-hydroxyl-7-deoxidation-7-(N-morpholino) daunomycinone
R 1=OH, R 2=H, R 3=OH, R 4=COCH 3, R 5=N (CH 2) 2OA63:4-demethoxylation-7,9-dideoxy-14-(N-morpholino) daunomycinone
R 1=R 3=R 3=R 5=H, R 4=COCH 2N (CH 2) 2OA64:4-demethoxylation-4-hydroxyl-14-(N-morpholino) daunomycinone
R 1＝R 3＝R 5＝OH，R 2＝H，R 4＝COCH 2N(CH 2) 2O
According to substituent character, can be by known anthrone through suitable chemical improvement preparation formula A chemical compound.The method of preparation formula A chemical compound and pharmaceutically acceptable salt thereof is as follows:
(I) a kind of preparation R wherein 1Be OR 6(R wherein 6As defined above), R 2Be hydrogen or COOCH 3, R 3Be OH, R 4Be C 1Or C 2Alkyl or COCH 3And R 5Be hydrogen, OH or OCOOC 2H 5Formula A chemical compound or its pharmacology on the method for optimizing of acceptable salt comprise:
(1) 6-, the 11-of chemical compound and the 7-hydroxyl that may exist shown in the protection following formula G:
R wherein bExpression hydrogen or COOCH 3, R cBe C 1Or C 2Alkyl or COCH 3, R eBe hydrogen or hydroxyl, thereby become derivant shown in the formula G1:
R wherein bAnd R cAs defined above, R ' eBe hydrogen or OCOOC 2H 5Group;
(2) make derivant demethylation shown in the formula G1 and make 4-hydroxy compounds shown in the formula G2 that is produced and formula R 6Halo derivatives suitable shown in the Hal reacts:
Figure A9519074300311
R wherein bAnd R cAnd R ' eAs defined above, R 6As defined above, Hal is a halogen, preferred iodine;
(3) make the 6-and the 11-phenolic hydroxyl group deblocking of the 4-O-alkyl derivative that is produced, thereby obtain chemical compound shown in the formula G3:
R wherein 6, R b, R cAnd R e' as defined above, and if desired, when R ' e is O-COOC 2H 5The time, make the 7-hydroxyl deblocking of chemical compound G3; With
(4) if need, the described formula A chemical compound that is produced is converted into its pharmaceutically acceptable salt.
(II) in another example, a kind of preparation R wherein 1Be formula OSO as defined above 2R 7Shown in group, R 2Be hydroxyl or COOCH 3, R 3Be OH, R 4Be C 1Or C 2Alkyl or COCH 3And R 5For the formula A chemical compound of hydrogen or hydroxyl or the method for optimizing of its pharmaceutically acceptable salt comprise: with suitable formula HalSO 2R 7Halo derivatives is handled anthrone shown in the formula H shown in (wherein Hal is a halogen, preferred chlorine atom):
Figure A9519074300321
R wherein bBe hydroxyl or COOCH 3, R cBe C 1Or C 2Alkyl or COCH 3And R eBe hydrogen or hydroxyl; With, if desired, gained formula A chemical compound is converted into its pharmaceutically acceptable salt.
(III) in another example, a kind of preparation R wherein 3Be OH, R 4Be COCH 3And R 5Be formula NR 9R 10(R wherein 9And R 10As defined above, condition is R 9Or R 10Can not be hydrogen or formula COR as defined above 11Or COOR 11Shown in group) shown in the formula A chemical compound of group or the method for optimizing of its pharmaceutically acceptable salt comprise: the glycoside unit and suitable formula NHR that make formula K 9R 10(R 9And R 10The reaction of amine derivative as defined above):
R wherein 1And R 2As defined above; With, if desired, the described formula A chemical compound that is produced is converted into acceptable salt on its pharmacology.
(IV) in another example, a kind of preparation R wherein 3Be OH, R 4Be COCH 3And R 5Be formula NR 9R 10(R wherein 9And R 10In one of be hydrogen atom, another is not hydrogen or formula COR as defined above 11Or COOR 11Shown in group) shown in the formula A chemical compound of group or the method for optimizing of its pharmaceutically acceptable salt comprise:
(1) the glycoside unit with above-mentioned formula K protects the 13-ethylenedioxy derivant that becomes formula K1:
Figure A9519074300331
R wherein 1And R 2As defined above;
(2) make above-mentioned formula K1 derivant and suitable formula NHR 9R 10(R 9And R 10The reaction of chemical compound as defined above);
(3) make the amino derivant 13-carbonyl deblocking that replaces of 7-of the formula K2 that is produced:
R wherein 1, R 2, R 9And R 10As defined above; With, if desired, described formula A chemical compound is converted into its pharmaceutically acceptable salt, for example acidify compd A and obtain acid-addition salts.
(V) in another example, a kind of preparation R wherein 3Be OH, R 4Be COCH 3And R 5Be formula NH 2Formula A chemical compound or the method for optimizing of its pharmaceutically acceptable salt comprise:
(1) with a kind of oxidizer treatment formula K2 derivant, wherein NR as defined above 9R 10Expression 3 ', 4 '-dimethoxy benzyl amino;
(2) make the 13-carbonyl deblocking of the 7-amino-substituted compounds of the formula K3 that is produced:
Figure A9519074300341
R wherein 1And R 2As defined above; With
(3) if need, can make the described formula A chemical compound that is produced be converted into its pharmaceutically acceptable salt, for example acidify compd A and obtain acid-addition salts.
(VI) in another example, a kind of preparation R wherein 3Be OH or H, R 4Be COCH 2NR 9R 10(R wherein 9And R 10As defined above, condition is that they can not be formula COR 11Or COOR 11Shown in group) and R 5For the formula A chemical compound of hydrogen or OH or the method for optimizing of its pharmaceutically acceptable salt comprise:
(1) incites somebody to action wherein R 1, R 2, R 3And R eFormula L chemical compound is converted into wherein R as defined above 1, R 2, R 3And R eThe 14-bromo derivative of corresponding formula L1 as defined above;
Figure A9519074300342
(2) make the 14-bromo derivative of formula L1 and suitable formula NHR 9R 10Shown amine reaction, wherein R 9And R 10As defined above, condition is that they can not be formula COR 11Or COOR 11Shown group; With
(3) if need, the described formula A chemical compound that is produced is changed into acceptable salt on its pharmacology, obtain acid-addition salts as the acidify compd A.
(VII) in another example, a kind of preparation R wherein 4Be formula COCH 2(wherein benzene (Ph) ring is randomly by nitro, amino or NR as defined above for O-Ph 9R 10Replacement) group and the R shown in 5For the method for optimizing of acceptable salt on the formula A chemical compound of hydrogen or hydroxyl or its pharmacology comprises:
(1) makes the reactant salt of formula L1 chemical compound and a kind of randomly substituted as mentioned above phenol, preferred nitrophenol as defined above; With
(2) if need, the described formula A chemical compound that is produced is converted into acceptable salt on its pharmacology.
(VIII) in another example, a kind of preparation R wherein 4Be formula XCH 2R 8(R wherein 8Be group shown in formula C and the D as defined above) shown in the formula A chemical compound of group or the method for optimizing of its pharmaceutically acceptable salt comprise:
Make at 9 bit strips hydroxylating side chain such as COCH are arranged 2OH or CH 2CH 2Derivatives reaction shown in the anthrone of OH and formula C ' or the D ':
(2) if need, the resulting ester derivant of hydrolysis, thus obtain being partly with the anthrone of the formula A of hydroxyl at acetal; With
(3) if need, the described formula A chemical compound that is produced is converted into its pharmaceutically acceptable salt.
(IX) in another example, a kind of preparation R wherein 4Be group CH 2CH 2R 8The method for optimizing of formula A chemical compound comprise:
(1) incites somebody to action as defined above wherein R 4Be formula COCH 2R 8Shown in the formula A chemical compound of group be converted into corresponding 13-hydazone derivative, preferred 13-[(4-fluorine) benzenesulfonyl] hydrazone;
(2), use Reducing agent to reduce above-mentioned hydazone derivative can freeze mode under the condition of quinone system character of A chemical compound; With
(3) if need, with the wherein R that is produced 4Be described CH 2CH 2R 8The described formula A chemical compound of group is converted into its pharmaceutically acceptable salt.
It should be noted, if desired, can by the combination said method or with the method for elbs reaction cycle compound or anthrone (referring to " Doxorubicin " of F.Arcamone, MedicinalChemistry Vol17, Acadmic Press, 1981) or with universal synthesis method (referring to " Advaneed Organic Reation " Fourth Ed. of J.March, J.Wiley﹠amp; Sons, 1992) to by method (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) derivant of the formula A of preparation further transform in the different piece of this molecule.For example wherein X be the CO group formula A chemical compound can X be the formula A chemical compound of CHOH by be converted into wherein with sodium borohydride reduction.R wherein 5For the formula A chemical compound of OH can be converted into R by handling with sodium dithionite 5Respective compound for H.
In (I) defined formula A chemical compound can as described in the DE-A-2750812 by for example following method preparation: make formula G chemical compound as defined above and excessive methylamino ethoxy acyl chlorides in pyridine in room temperature reaction 1-2 hour, use aluminium bromide processing protected derivant G13-6 hour under room temperature in exsiccant aprotic solvent (preferred dichloromethane) then; Preferably use formula R 6The iodo derivative of I in aprotic solvent such as dichloromethane or chloroform and in the presence of condensing agent (preferred silver oxide) under 40-60 ℃ of temperature to the 4-hydroxy derivatives alkylation of the formula G2 that produced 6-24 hour; Then by at first using morpholine in polar aprotic solvent (as methanol), to remove the hydroxyl deblocking that the very rare sodium hydrate aqueous solution hydrolysis 7-O-carbethoxyl group of phenol protecting group, reuse (if the words that exist) makes formula G3 chemical compound in room temperature treatment 1-3 hour.
Defined formula A chemical compound can prepare by for example following method as described in US-A-4965351 in (II); Formula H chemical compound is dissolved in exsiccant aprotic solvent such as the dichloromethane and uses formula HalSO as defined above as defined above 2R 7Chemical compound (Hal is a halogen, preferred chlorine) is at organic base such as N, and the 4-dimethylamino naphthyridine of N-diisopropylethylamine and catalytic amount exists down, under 0-30 ℃ of temperature, preferably at room temperature handles secondary somewhat to several hours.
Defined formula A chemical compound can prepare by the following method in (III): make formula K chemical compound and formula NHR as defined above as defined above 9R 10Shown amine derivative is in exsiccant aprotic solvent such as anhydrous methylene chloride, and reaction is several hours to several days under 10-30 ℃ temperature; With, if desired, preferably use anhydrous hydrogen chloride acidify products therefrom in methanol, obtain acid-addition salts.
Defined formula A chemical compound can prepare by the following method in (IV): making as defined above, formula K chemical compound and ethylene glycol reacted 3-6 hour in reflux temperature in the presence of acid catalyst (preferred p-methyl benzenesulfonic acid) in toluene; Then, make protected derivant K1 and formula NHR as defined above 9R 10Chemical compound preferably at room temperature reacted 1 to several days in polar solvent such as pyridine or oxolane; Adding several methoxybenzene with trifluoroacetic acid then preferably at room temperature handles the derivant 30 minutes to 2 hours of formula K2 and makes protected carbonyl deblocking; With, if desired, preferably the chemical compound that is produced is converted into acid-addition salts with the anhydrous hydrogen chloride that is dissolved in the methanol.
Defined formula A chemical compound can prepare by for example following method in (V): make as defined above wherein NR 9R 10Expression 3, the formula K2 chemical compound and 2 of 4-dimethoxy benzyl amino, 3-two chloro-5,6-dicyano-1,4-benzoquinone (DOQ) room temperature reaction one day in water and dichloromethane mixture; At room temperature as mentioned above the derivant of the formula K3 that produced is carried out 1 deblocking when advancing for a short time with trifluoroacetic acid and methoxybenzene then; With, if desired, preferably the chemical compound that is produced is converted into acid-addition salts with the anhydrous hydrogen chloride that is dissolved in the methanol.
In (VI) defined formula A chemical compound as described in the DE-A-2557537 by for example following method preparation: make the formula L1 chemical compound that makes by compound L by DE-A-1917874 and suitable formula NHR 9R 10(R wherein 9And R 10As defined above, condition is R 9And R 10Be not foregoing formula COR 11Or COOR 11Shown in group) shown in amine in exsiccant polar solvent such as acetone or dimethyl formamide, under about 20-60 ℃ temperature, reacted 4-24 hour; With, if desired, preferably the gained chemical compound is converted into acid-addition salts with the anhydrous hydrogen chloride that is dissolved in the methanol.
In (VII) defined formula A chemical compound can as described in the DE-A-1917874 by for example following method preparation: make as defined above formula L1 chemical compound and phenol derivatives as defined above in aprotic organic solvent such as acetone in the presence of alkali (preferred potassium carbonate or sodium), under 20-60 ℃ temperature, react.
Defined formula A chemical compound can be as preparation as follows as described in WO92/10212 and the WO92/02255 in (VIII): the derivant that for example makes anthrone and formula C ' and D ' as defined above is in the presence of acid catalyst such as the p-methyl benzenesulfonic acid pyridine, in aprotic solvent such as dichloromethane, under 10-30 ℃ the temperature, preferably reacted 3-24 hour under the room temperature; With, if desired, with this ester derivant of dilute sodium hydroxide aqueous solution hydrolysis.
Defined formula A chemical compound can be as preparation as follows as described in the GB-A-2238540 in (IX): for example with sodium cyanoborohydride in organic solvent such as toluene or dimethyl formamide under 25-80 ℃ of temperature the 13-[(4-fluorine of the anthrone of formula A as defined above) benzenesulfonyl] hydazone derivative reduction 6-24 hour.
Some starting material that is used for preparation formula A chemical compound is known.Other starting materials can be made from known compound by known method similarly.
For example, following compounds is known and can be represented by identical formula A:
Daunomycinone (R 1=OCH 3, R 2=H, R 3=R 5=OH, R 4=COCH 3)
Adriamycinone (R 1=OCH 3, R 2=H, R 3=R 4=OH, R 5=COCH 2OH)
4-demethoxylation daunomycinone (R 1=R 2=H, R 3=R 5=OH, R 4=COCH 3)
Fuchsin ketone (R 1=OH, R 2=H, R 3=R 5=OH, R 4=COCH 3)
β-rhodomycinon (R 1=R 2=R 3=R 5=OH, R 4=CH 2CH 3)
ε-rhodomycinon (R 1=R 3=R 5=OH, R 2=COOCH 3, R 4=CH 2CH 3)
Corresponding 7-deoxidation derivative (R 5=H) the sugar derivatives shown in (referring to " Doxoru-bicin " of F.Arcamone, Medicinal Chemistry, Vol.17, Academic Press, 1981) or the formula M:
Figure A9519074300391
As the gentle mould sugar of aminosaccharide, 3-amino-2,3,6-three deoxidations-L-pyrans lyxose (M1:R 3=NH 2, R t=R x=OH, R u=H) (referring to J.Am.Chem.Soc., 86,5334,1964) or acosamine, 3-amino-2,3,6-three deoxidations-L-arabopyranose (M2:R s=NH 2, R u=R x=OH, R t=H) (referring to J.Am.Chem.18,703,1975) or corresponding 1-chloro-3,4-two (trifluoroacetyl group) mould sugar derivatives (R that softens x=Cl and R s=NHCOCF 3, R t=OCOCF 3) or 1-chloro-3,4-two (trifluoroacetyl group) acosaminyl derivant (R x=Cl and R s=NHCOCF 3, R u=O-COCF 3).
The feature of The compounds of this invention is active to the height inhibition of amyloidosis.
Term " amyloidosis " refers to have following common trait in disease: specified protein tends to polymerization and precipitation to be become insoluble fibril and enters extracellular space, and the 26S Proteasome Structure and Function of organ and tissue is caused damage.The classification of amyloid and amyloidosis is recently at (World Health Organization's communique) (Bulletin of the World Health Organisation 71 (1): revise in 105 (1993).
All dissimilar amyloids all have identical ultrastructure tissue in antiparallel beta sheet layer, although they contain many protein subunits that differ widely [referring to Glenner G.G., New England J.Med.302 (23) 1283﹠amp; 1980) the .Al amyloidosis is to be caused by the special monoclonal immunoglobulin light chain that can form amyloid fibrils.These monoclonal light chains are to be produced by the low monoclonal plasma cell of mitotic index, and they have the reason of known insensibility to chemotherapy just and mitotic index is low.The toxicity of these cells is their albumen synthesizing activity.
The clinical disease course of these diseases depends on the selectivity that organ involves; Prognosis totally unfavorable (mean survival time＜12 month) under heart infiltration situation, and involve comparatively favourable under the situation (surviving average time about 5 years) at kidney.
The deposit of considering the amyloid generation is to quite insensitive, and the amyloid that can prevent or slow down forms also increases AL amyloidosis patient's the unique rational hope seemingly of the deliquescent molecule of existing amyloid beta deposition thing.In addition; because the fibriilar supermolecule tissue of amyloid is identical to all types of amyloids; so provide to disturb amyloid to form and increase and have the deliquescent medicine of deposit (removing) through normal mechanism; may be all very favourable to all types of amyloidosis, in particular for treatment Alzheimer disease.
In fact, the main pathological characters of Alzheimer disease (AD), Down syndrome, Pugilistica dementia and brain amyloid blood vessel disease is in brain essence and blood vessel wall amyloid beta deposition to take place.These features are relevant with nerve cell death in cortex, marginal zone and the inferior cortex nuclear.Several studies show that, the various neural selective injury in the preceding cortex descends relevant with the synapse loss with cognition.The pathogenesis of nerve degeneration process and molecular basis are not clear among the AD, but the effect of sedimentary amyloid-beta is given prominence to (yanker etc. with external neurovirulent nearest report in vivo by relevant its in brain essence and blood vessel wall, Scieme, 245:174,1990.Kowall etc., PNAS 88:7247,1991).In addition, by amyloid precursor protein (APP) gene mutation the separation of common AD has been caused the interest [Mullan M. etc., YINS, 16 (10): 392 (1993)] of people to amyloid-beta potential pathogenic effects in AD.
The neurotoxicity of amyloid-beta is relevant with proteinic fibril formation performance.With the synthetic peptide of homology studies show that hippocampal cell in being exposed to fresh β 1-42 solution 24 hours insensitive, and when neuron when 37 ℃ of following exposures have been stored in the saline solution 2-4 days β 1-42, its viability reduces, and stores to help peptide aggregation in saline.Relation between fibril and neurotoxicity obtains nearest data and further supports, this data shows, the solubility amyloid-beta in normal cellular process in vivo with external generation (Hass etc., Nature, 359,322,1993), and have only that to have a liking for the Congo (Congophilic) just relevant with distrophic nevrites when assembling in forming when it.On the other hand, contain the non-amyloid formation and neuronal degeneration irrelevant (Tagliavini etc., Neurosci.Lett.93:191,1988) of having a liking for the Congo of unimolecule amyloid beta.
The neurotoxicity of amyloid-beta also is confirmed by the peptide homologue amyloid-beta segment 25-35 (β 25-35) that use remains with the self aggregation performance of complete amyloid-beta fragment β 142.
With hippocampal neuron for a long time but not be exposed to the β 25-35 of micro-molar concentration in short time, the programmed cell death mechanism that is known as apoptosis (apoptosis) by activation is induced nerve cell death (Forloni etc., NeuroReport, 4:523,1993,1993).This moment, neurotoxicity was still relevant with the self aggregation performance of β 25-35.
The feature of other nerve degeneration diseases such as spongiform encephalopathy (SE) is the extracellular deposition of nerve cell death and amyloid, and the amyloid of this moment derives from prion protein (Prp).To have a neurovirulent observation similar to amyloid-beta, research and the influence of the homologous synthetic peptide of the different segments of Prp to the viability of the Mus hippocampal neuron of coming into being.The long-time peptide of using corresponding to Prp106-126 has brought out nerve cell death by apoptosis, and under the same conditions, the peptide of all other tests and the tangled sequence of Prp106-126 do not reduce cell viability (Forloui etc., Nature 362:543).Prp106-126 has the height fibrillation external, and when using congo red staining, the peptide aggregation body surface reveals the green biifrangence of the β-layer conformational characteristic that shows amyloid.
The compounds of this invention can be used to prepare the medicine of the development of the disease that is used to prevent or suppresses to be caused by amyloid such as AL amyloidosis, Alzheimer disease or Down syndrome etc.
The present invention also comprises in its scope and comprises the pharmaceutical composition that one or more compd As are made active component and necessary pharmaceutically acceptable carrier, excipient or additive.
The pharmaceutical composition that contains formula A compound or its salt can be made various dosage forms by using conventional nontoxic pharmaceutical carrier to amass diluent according to a conventional method, and with various administering mode administrations.
Specifically, formula A chemical compound administration as follows: A oral administration, for example tablet, lozenge, lozenge, aqueous suspensions or oil suspension, but dispersion powder or granule, Emulsion, hard or soft capsule or syrup or elixir.Be used for the known method preparation that liquid preparations for oral administration can be used to make pharmaceutical composition by prior art, and these compositionss can contain the reagent that one or more are selected from sweeting agent, flavouring agent, coloring agent and antiseptic, the preparation that can swallow to provide pharmaceutically refined.
Tablet contains active component and is suitable for making the nontoxic pharmaceutically acceptable excipient of tablet.These excipient can be, for example inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example corn starch or alginic acid; Binding agent is as corn starch, gelatin or arabic gum and lubricant, as magnesium stearate or stearic acid or Talcum.Tablet can not add coating or available known technology applies, and with disintegrate and the absorption of delay in intestines and stomach, thereby provides continuous action in the long period.For example, the up time postpones material such as glyceryl monostearate or glycerol distearate.The preparation that is used for oral administration also can be made into hard gelatin capsule, wherein active component mixes with inert solid diluent such as calcium carbonate, calcium phosphate or Kaolin, or make Perle, wherein active component and water or oily medium such as Oleum Arachidis hypogaeae semen, paraffin oil or mixed with olive oil.Aqueous suspensions contains active substance and is suitable for making the excipient of aqueous suspensions.
This type of excipient is a suspending agent, as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and arabic gum: dispersion or wetting agent can be natural phospholipids, as lecithin, or the condensation product of oxyalkylene and fatty acid, as Myrj 45, or the condensation product of ethylene oxide and long chain aliphatic, as 17 inferior ethoxyl hexadecanols, or ethylene oxide and derive from fatty acid and the condensation product of the part ester of the part ester of sugar alcohol, as octadecanoic acid ester of polyethylene glycol, or ethylene oxide and derive from fatty acid and the condensation product of the part ester of hexitol dehydrate, as polyoxyethylene sorbitan monooleate dehydration.Described aqueous suspensions also can contain one or more antiseptic, as ethylparaben or n-propyl, and one or more coloring agent, one or more flavoring agents, or one or more sweeting agents are as sucrose or glucide.Oil suspension can be by being suspended in active component in vegetable oil such as Oleum Arachidis hypogaeae semen, olive oil, in Oleum sesami or the Oleum Cocois or be suspended in mineral oil such as the paraffin oil and prepare.This oil suspension can contain thickening agent, as Cera Flava, hard paraffin or spermol.Can add aforesaid sweeting agent and flavoring agent, so that the oral formulations that can swallow to be provided.These compositionss can be preserved by adding a kind of autoxidator such as ascorbic acid.But being suitable for by adding dispersion powder and the granule that water prepares aqueous suspensions is the mixture of active component and dispersant or wetting agent, suspending agent and one or more antiseptic.The example of suitable dispersant or wetting agent and suspension be above-mentioned those.Can also there be other excipient, for example, sweet taste and flavoring agent.
Pharmaceutical composition of the present invention can also be oil-in-water emulsion.Oil phase can be a vegetable oil, for example olive oil or Oleum Arachidis hypogaeae semen, or mineral oil such as paraffin oil or its mixture.
Suitable emulsifying agent can be a natural gum, for example arabic gum or Tragacanth, natural phospholipid, Semen sojae atricolor for example, lecithin, and the ester or the part ester that derive from fatty acid and hexitol dehydrate, for example single oleic acid Isosorbide Dinitrate, with the condensation product of above-mentioned part ester and oxirane, for example polyoxyethylene sorbitan monooleate dehydration.Emulsion also can contain sweeting agent and flavoring agent.Syrup and elixir can prepare with sweeting agent such as glycerol, sorbitol or sucrose.This type of preparation also can contain demulcen, antiseptic and flavoring agent and coloring agent.
B, with sterile injectable water or oil suspension form parenteral, but subcutaneous administration, or administration in intravenous administration or intramuscular administration or the breastbone, perhaps use the transfusion administration.This pharmaceutical composition can be sterile injectable water or oil suspension form.
These suspensions can be prepared with those above-mentioned suitable dispersions or wetting agent and suspending agent by known technology.Sterile injectable preparation also can be at nontoxic parenteral acceptable diluent or sterile injectable solution or the suspension in the solvent, as 1,3 butylene glycol solution.In these acceptable excipient and solvent, spendable have water, Ringer's mixture and an isotonic sodium chlorrde solution.In addition, usually aseptic fixedly oil is used as solvent or suspension media.
For this reason, can use the bland fixedly oil that comprises synthetic single or two glyceride usually.In addition, fatty acid such as oleic acid are used to prepare injection.
An also purpose of the present invention provides a kind of method of controlling amyloidogenic disease by reactive compound shown in one or more formulas A that gives the patient's administering therapeutic effective dose that needs this treatment.
According to the type and the order of severity of the activity of specific compound, patient's age to be treated, body weight and condition, disease, and the frequency of administration and approach, daily dose is in about 0.1-50mg/kg weight range; Preferred daily dose is in the 5mg-2g scope.The amount with the active component of production unit dosage forms of can mixing with carrier mass is with being become by treatment patient and concrete form of medication.For example, be used for oral preparation and can comprise 5mg-2g activating agent and suitable carriers material, this carrier accounts for the 5-95% of total composition.The per unit dosage forms contains the active component of the about 500mg of 5mg-that has an appointment usually.
Following embodiment will illustrate the present invention, rather than restriction the present invention.
The preparation of embodiment 1:14-(N-morpholino) daunomycinone (A1)
Will be by J.Org.Chem., and the 14-bromo daunomycinone of 42,3653 (1977) described preparations (L1 ': R 1=OCH 3, R 2=H, R 5=OH) (0.95g 2mmol) is dissolved in the anhydrous methylene chloride (50ml), and (0.34g, 4mmol) processing also at room temperature kept 24 hours with morpholine.Afterwards, removal of solvent under reduced pressure, and use the mixture (90: 10 of dichloromethane and acetone, volume ratio) makes eluent and on silica gel, crude product is carried out the flash chromatography separation, obtain title compound A1, the hydrogen chloride methanol solution that adds stoichiometric amount is translated into corresponding hydrochlorate (0.8g, productive rate: 77%), use ether sedimentation then.Use Kieselgel F 254(Merck) carry out thin layer chromatography analysis (TLC), development system is methylene chloride acetone (9: 1, volume ratio), Rf=0.5.
FD-MS:m/e 483[M] + 1HNMR (200MHz, DMSO-d 6) δ: 2.03 (dd, J=4.5,14.2Hz, 1H, H-8ax); 2.32 (d, J=14.2Hz, 1H, H-8eq); 2.95 (d, J=18.5Hz, 1H, H-10ax); 3.17 (d, J=18.5Hz, 1H, H-10eq); 3.2,3.5 (m, 4H ,-CH 2-N-CH 2-); 3.7,4.0 (m, 4H ,-CH 2-O-CH 2-); 4.02 (s, 3H, OCH 3); 4.87 (m, 2H, CH 2-14); 5.16 (m, 1H, H-7); 5.70 (bandwidth signals, 1H, OH-7); 6.36 (s, 1H, OH-9); 7.68 (m, 1H, H-3); 7.93 (m, 2H, H-1+H-2); 10.40 (bandwidth signals, 1H, NH +); 13.29 (s, 1H, OH-11); 14.01 (s, 1H, OH-6).
The preparation of embodiment 2:7-deoxidation-7-(N-morpholino) daunomycinone (A30)
Will be by DE-A-2, and the 7-carbethoxyl group daunomycinone of 750,812 described preparations (K ': R 1=OCH 3, R 2=H) (0.94g 2mmol) is dissolved in the mixture of dichloromethane (50ml) and methanol (5ml), adds morpholine (3ml) and mixture was at room temperature kept 20 hours.Afterwards, removal of solvent under reduced pressure, the mixture of use dichloromethane and acetone (95: 5, volume ratio) makes eluent system and on silica gel, crude product is carried out the flash chromatography separation, obtain title compound A30, convert it into corresponding hydrochlorate 10.5g, productive rate by the methanolic hydrogen chloride liquid that adds stoichiometric amount: 53%), the reuse ether sedimentation.
Use Kieselgel F 254(Merck) carry out TLC and analyze, expanding body is dichloromethane/acetone (9: 1, volume ratio), Rf=0.58FD-MS:m/e 467[M]+ 1HNMR (200MHz, CDCl 3) δ: 1.77 (dd, J=3.3,14.5Hz, 1H, H-8ax); 2.32 (dd, J=2.0,14.5Hz, 1H, H-8eq); 2.40 (s, 3H, COCH 3); 2.50,3.00 (m, 4H ,-CH 2-N-CH 2-); 3.10,3.20 (Abq, J=18.7Hz, 2H, CH 2-10); 3.64 (m, 4H ,-CH 2-O-CH 2-); 4.08 (s, 3H, OCH 3); 4.35 (dd, J=2.0,3.3Hz, 1H, H-7); 7.38 (d, J=8.3Hz, 1H, H-3); 7.78 (dd, J=7.7,8.3Hz, 1H, H-2); 8.02 (d, J=7.7Hz, 1H, H-1); 13.29 (s, 1H, OH-11); 14.11 (s, 1H, OH-6).
Embodiment 3:7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino)-preparation of 13-deoxidation-13-ethylenedioxy daunomycinone (A32)
Will by the 7-carbethoxyl group daunomycinone of preparation as mentioned above (K ': 1.88g, 4mmol) be dissolved in the toluene (100ml), add ethylene glycol (3ml) and p-methyl benzenesulfonic acid pyridiniujm (0.1g).Used Dean-Stark trap backflow mixture 6 hours, and removed and anhydrate.Afterwards, the room temperature reaction mixture is with 1% sodium bicarbonate aqueous solution and water washing.Organic facies is removed organic solvent with anhydrous sodium sulfate drying and decompression, obtains 13-ethylenedioxy derivant K ' (0.92g).
Use Kieselgel F 254(Merck) carry out TLC and analyze, expanding body is dichloromethane/acetone (9: 1, volume ratio), Rf=0.25 FD/MS:m/e 518[M] +
(0.85g 1.64mmol) is dissolved in the mixture of pyridine (20ml) and anhydrous tetrahydro furan (20ml), adds 3, and 4-dimethoxybenzylamine (1ml) also at room temperature kept 2 days with 13-ethylenedioxy derivant K '.Afterwards, use dichloromethane (100ml) diluted reaction mixture, and wash with 1N sodium-chloride water solution, water and 1% sodium bicarbonate aqueous solution.Separate organic facies, removal of solvent under reduced pressure.The mixture of use dichloromethane and acetone (95: 5, volume ratio) makes eluent system and on silica gel, thick product is carried out the flash chromatography separation, obtain title compound A32, the methanolic hydrogen chloride liquid that adds stoichiometric amount is translated into corresponding hydrochlorate, uses ether sedimentation.
Use Kieselgel F 254(Merck) carry out TLC and analyze, expanding body is dichloromethane/acetone (9: 1, volume ratio), Rf=0.8
FD-MS：m/e?607[M]+ 1HNMR(200MHz，CDCl 3)δ：1.49(s，3H，CH 3)；1.62(dd，J＝4.0，14.2Hz，1H，H-8ax)；2.45(ddd，J＝1.8，1.8，14.2Hz，1H，H-8eq)；2.86(d，J＝19.1Hz，1H，H-10ax)；3.21(dd，J＝1.8，19.1Hz，1H，H-10eq)；3.85，3.88(2xs，6H，OCH 3)；4.06(s，7H，4-OCH 3+-O-CH 2-CH 2-O-)；4.44(dd，J＝1.8，4.0Hz，1H，H-7)；6.8-6.9(m，3H，H-2’+H-5’+H-6’)；7.34(dd，J＝1.0，8.5Hz，1H，H-3)；7.75(dd，J＝7.8，8.5Hz，1H，H-2)；8.01(dd，J＝10，7.8Hz，1H，H-1)
Embodiment 4:7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino) preparation of daunomycinone (A36)
To be dissolved in as the compound A-13 2 (0.3g) of preparation as described in the embodiment 3 in the trifluoroacetic acid (3ml), add a methoxybenzene.Use the dichloromethane diluted reaction mixture after one hour,, use anhydrous sodium sulfate drying with the washing of 1% sodium bicarbonate aqueous solution.Organic solvent is removed in decompression, used dichloromethane and methanol mixture (95: 5, volume ratio) makes eluent system and on silica gel, crude product is carried out the flash chromatography separation, obtain 7-deoxidation-7-(3 ', 4 '-dimethoxy benzyl amino) daunomycinone (A36), add the methanolic hydrogen chloride liquid of stoichiometric amount, be translated into corresponding hydrochlorate, use ether sedimentation then.
Use Kieselgel F 254(Merck) carry out TLC and analyze, expanding body is methylene chloride (8: 2, volume ratio), Rf=0.5.2.02 (dd, J=5.0,14.4Hz, 1H, H-8ax); 2.34 (s, 3H, COCH 3); 2.48 (m, 1H, H-8eq); 2.98,3.08 (Abq, J=19.0Hz, 2H, CH 2-10); 3.74,3.78 (2xs, 6H, OCH 3); 4.00 (s, 3H, 4-OCH 3); 4.35 (m, 2H, NH-CH 2-aryl; 4.59 (m, 1H, H-7); 6.80 (bandwidth signals, 1H, OH-9); (6.99 d, J=8.1Hz, 1H, H-5 '); (7.15 d, J=8.1Hz, 1H, H-6 '); (7.31 s, 1H, H-2 '); 7.69 (m, 1H, H-3); 7.92 (m, 2H, H-1+H-2); 8.5,8.9 (bandwidth signals, 2H, NH 2 +); 12.99 (bandwidth signals, 1H, OH-11); 13.94 (bandwidth signals 1H, OH-6).
The preparation of embodiment 5:7-deoxidation-7-benzyl amino-13-deoxidation-13-ethylenedioxy daunomycinone (A33)
Will (0.85g 1.64mmol) in the mixture of dichloromethane (40ml) and methanol (4ml), handles and at room temperature kept 18 hours with benzylamine (0.5ml) as the 13-ethylenedioxy derivant K1 ' of preparation as described in the embodiment 3.Afterwards, removal of solvent under reduced pressure, the mixture of use dichloromethane and acetone (9: 1, volume ratio) makes eluent system and on silica gel, crude product is carried out flash chromatography, obtain title compound A33 (0.55g), the methanolic hydrogen chloride liquid that adds stoichiometric amount is translated into corresponding hydrochlorate, uses ether sedimentation then.At Kieselgel F 254(Merck) carry out TLC and analyze, expanding body is dichloromethane/acetone (9: 1, volume ratio), Rf=0.20
The preparation of the amino daunomycinone of embodiment 6:7-deoxidation-7-benzyl (A37)
As handling compound A-13 3 with trifluoroacetic acid as described in the embodiment 4 as preparation as described in the embodiment 5, obtain the amino daunomycinone (A37) of 7-deoxidation-7-benzyl, the methanolic hydrogen chloride liquid that adds stoichiometric amount is translated into corresponding hydrochlorate, uses ether sedimentation then.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is dichloromethane/acetone (9: 1, volume ratio), Rf=0.60FD-MS:m/e 487[M]+ 1HNMR (200MHz, CDCl 3) δ: 1.76 (dd, J=4.1,14.4Hz, 1H, H-8ax); 2.33 (ddd, J=1.7,1.9,14.4Hz, 1H, H-8eq); 2.42 (s, 3H, COCH 3); 2.88 (d, J=18.8Hz, 1H, H-10ax); 3.14 (dd, J=1.9,18.8Hz, 1H, H-10eq); 3.91,4.08 (Abq, J=12.4Hz, 2H, NH-CH 2-aryl); 4.04 (s, 3H, 4-OCH 3); 4.41 (dd, J=1.7,4.1Hz, 1H, H-7); 7.3-7.4 (m, 6H, C 6H 5-+H-3); 7.72 (dd, J=7.8,8.5Hz, 1H, H-2); 7.94 (dd, J=1.1,7.8Hz, 1H, H-1); 13.20 (bandwidth signals, 1H, OH-11) 13.40 (bandwidth signals, 1H, OH-6).
The preparation of embodiment 7:7-deoxidation-7-(2 '-hydroxyl ethylamino)-B-deoxidation generation-13-ethylenedioxy daunomycinone (A34)
Title compound A34 presses embodiment 3 described method preparations, but uses ethanolamine.At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (9: 1, volume ratio), Rf=0.2 1HNMR (200MHz, CDCl 3) δ: 1.45 (s, 3H, CH 3); 1.57 (dd, J=4.1,14.1Hz, 1H, H-8ax); 2.37 (ddd, J=1.4,1.4,14.1Hz, 1H, H-8eq); 2.80 (d, J=19.0Hz, 1H, H-10ax); 3.03 (m, 2H, NH-CH 2-CH 2-OH); 3.11 (dd, J=1.4,19.0Hz, 1H, H-10eq); 3.6-4.0 (m, 2H, NH-CH 2-CH 2-OH); 3.99 (s, 3H, OCH 3); 4.04 (s, 4H ,-O-CH 2-CH 2-O-); 4.34 (m, 1H, H-7); 7.29 (d, J=7.7Hz, 1H, H-3); 7.69 (dd, J=7.7,7.7Hz, 1H, H-2); 7.88 (d, J=7.7Hz, 1H, H-1).
The preparation of embodiment 8:7-deoxidation-7-(2 '-hydroxyethylamino) daunomycinone (A38)
Title compound A38 presses embodiment 4 described methods by compound A-13 4 preparations.At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (9: 1, volume ratio), Rf=0.5 FD-MS:m/e 441[M] + 1HNMR (200MHz, CDCl 3) δ: 1.80 (dd, J=4.2,14.4Hz, 1H, H-8ax); 2.28 (ddd, J=1.8,2.0,14.4Hz, 1H, H-8eq); 2.41 (s, 3H, COCH 3); 2.96 (d, J=18.5Hz, 1H, H-10ax); 3.03 (m, 2H, NH-CH 2-CH 2-OH); 3.20 (dd, J=1.8,18.5Hz, 1H, H-10eq); 3.5-4.0 (m, 2H, NH-CH 2-CH 2-OH); 4.08 (s, 3H, OCH 3); 4.45 (dd, J=2.0,4.2Hz, 1H, H-7); 7.39 (J=1.0,8.5Hz, 1H, H-3); 7.78 (J=7.7,8.5Hz, 1H, H-2); 8.03 (dd, J=1.0,7.7Hz, 1H, H-1).
The preparation of the amino daunomycinone of embodiment 9:7-deoxidation-13-ethylenedioxy-7-(A40)
Will by the 7-deoxidation-7-of embodiment 3 described preparations (3 ', 4 '-dimethoxy benzyl amino)-13-deoxidation generation-13-ethylenedioxy daunomycinone (A32,0.5g) be dissolved in the mixture of dichloromethane (80ml) and water (4ml), add 2,3-two chloro-5,6-dicyano-1 also at room temperature kept 24 hours in the 4-benzoquinone (DDQ).Use 1% sodium bicarbonate aqueous solution washing reaction mixture then.Separate organic facies and removal of solvent under reduced pressure, obtain title compound A40 (0.3g).At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is dichloro alkylene/methanol (6: 1, volume ratio), Rf=0.25
The preparation of the amino daunomycinone of embodiment 10:7-deoxidation-7-(A42)
Press the embodiment 4 described compd As 40 (0.2g) of pressing embodiment 9 preparations of handling with trifluoroacetic acid, used dichloromethane and methanol mixture (95: 5, volume ratio) carrying out obtaining the amino daunomycinone (A42 of 7-deoxidation-7-after flash chromatography separates on the silica gel, 0.14g), the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate, uses ether sedimentation then.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (6: 1, volume ratio), Rf=0.33FD-MS:m/e 397 [M]+ 1HNMR (200MHz, DMSO-d 6) δ: 1.79 (dd, J=5.3,14.9Hz, 1H, H-8ax); 2.02 (d, J=14.9Hz, 1H, H-8eq); 2.29 (s, 3H, COCH 3); 2.76 (d, J=18.6Hz, 1H, H-10ax); 2.89 (d, J=18.6Hz, 1H, H-10eq); 3.96 (s, 3H, 4-OCH 3); 4.31 (d, J=5.3Hz, 1H, H-7); 7.60 (m, 1H, H-1+H-2); 8.00 (bandwidth signals, 2H, NH 2).
The preparation of embodiment 11:14-(N-piperidino) daunomycinone (A2)
Will be by J.Org.Chem., and the 14-bromo daunomycinone of 42,3653 (1977) described preparations (L1 ': R 1=OCH 3, R 2=H, R 5=OH) (0.95g 2mmol) is dissolved in the anhydrous methylene chloride (50ml), and (0.34g, 4mmol) processing also at room temperature kept 16 hours with piperidines.Removal of solvent under reduced pressure then, with dichloromethane and methanol mixture (96: 4, volume ratio) makes eluent system and on silica gel, crude product is carried out the flash chromatography separation, obtain title compound, the methanolic hydrogen chloride liquid that adds stoichiometric amount is translated into corresponding hydrochlorate (0.55g, productive rate: 53%), the reuse ether sedimentation.At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (9: 1, volume ratio), Rf=0.5).FAB-MS:m/e 482[M+H] + 1H-NMR (200MHz, DMSO-d6) δ: 1.2-1.9 (m, 6H, piperidines CH 2-3+CH 2-4+CH 2-5); 1.97 (dd, J=4.6,14.1Hz, 1H, H-8ax); 2.30 (d, J=14.1Hz, 1H, H-8eq); 2.89 (d, J=18.4Hz, 1H, H-10ax); 3.0,3.4 (m, 4H, piperidines CH 2-1+CH 2-6); 3.13 (d, J=18.4Hz, 1H, H-10eq); 3.97 (s, 3H, OCH 3-4); 4.76 (m, 2H, CH 2-14); 5.10 (m, 1H, H-7); 5.60 (d, J=6.6Hz, 1H, OH-7); 6.39 (s, 1H, OH-9); 7.64 (m, 1H, H-3); 7.90 (m, 2H, H-1+H-2); 9.7 (bandwidth signals, 1H, HN +); 13.23 (s, 1H, OH-11); 13.95 (s, 1H, OH-6)
Embodiment 12:14-[N-(N '-methyl) piperazine-1-yl] preparation of daunomycinone (A4)
Title compound is pressed embodiment 1 and 2 described preparations similarly.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (8: 2, volume ratio), Rf=0.36.FAB-MS:m/e=497[M+H] + 1H-NMR (200MHz, CDCl 3) δ: 2.14 (dd, J=4.8,14.5Hz, 1H, H-8ax); 2.32 (s, 3H, NCH 3); 2.36 (ddd, J=2.0,2.0,14.5Hz, 1H, H-8eq); (2.4-2.7 m, 8H, piperazine hydrogen); 2.98 (d, J=18.5Hz, 1H, H-10ax); 3.17 (dd, J=2.0,18.5Hz, 1H, H-10eq); 3.60,3.72 (two doublets, J=16.7Hz, 2H, CH 2-14); 4.0 (bandwidth signals, 1H, OH-7); 4.09 (s, 3H, OCH 3-4); 5.27 (dd, J=2.0,4.8Hz, 1H, H-7); 6.1 (bandwidth signals, 1H, OH-9); 7.39 (dd, J=1.1,8.6Hz, 1H, H-3); 7.78 (dd, J=7.7,8.6Hz, 1H, H-2); 8.02 (dd, J=1.1,7.7Hz, 1H, H-1); 13.31 (bandwidth signals, 1H, OH-11); 13.97 (s, 1H, OH-6)
Embodiment 13:14-[N-lignocaine] preparation of daunomycinone (A58)
Title compound is pressed embodiment 1 and 2 described preparations similarly.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (9: 1, volume ratio), Rf=0.45.FAB-MS:m/e=470[M+H] + 1H-NMR (200MHz, CDCl 3) δ: 1.15 (t, J=7.2Hz, 6H, N (CH 2CH 3) 2); 2.14 (dd, J=4.8,14.5Hz, 1H, H-8ax); 2.37 (ddd, J=2.0,2.0,14.5Hz, 1H, H-8eq); 2.69 (m, 4H, N (CH 2CH 3) 2); 2.97 (d, J=18.5Hz, 1H, H-10ax); 3.21 (dd, J=2.0,18.5Hz, 1H, H-10eq); 3.58,3.73 (two doublets, J=15.4Hz, 2H, CH 2-14); 4.08 (s, 3H, OCH 3-4); 5.23 (dd, J=2.0,4.8Hz, 1H, H-7); 7.38 (dd, J=1.0,8.3Hz, 1H, H-3); 7.76 (dd, J=7.7,8.3Hz, 1H, H-2); 8.02 (dd, J=1.0,7.7Hz, 1H, H-1); 13.3 (bandwidth signals, 1H, OH-11); 14.0 (bandwidth signals, 1H, OH-6)
The preparation of embodiment 14:4-demethoxylation-14-(N-morpholino) daunomycinone (A10)
Title compound is pressed embodiment 1, and described the latter presses J.Org.Chem. by 4-demethoxylation-14-bromo daunomycinone preparation, and 42,3653 (1977) the described methods that are used for daunomycinone are obtained by the bromination of 4-demethoxylation daunomycinone.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (96: 4, volume ratio), Rf=0.21.FAB-MS:m/e 454[M+H] + 1H-NMR (200MHz, DMSO-d6) δ: 1.96 (dd, J=4.6,14.3Hz, 1H, H-8ax); 2.16 (dd, J=2.0,14.3Hz, 1H, H-8eq); 2.44 (m, 4H, N (CH 2CH 2) 2O); 2.92,3.00 (two doublets, J=18.7Hz, 2H, CH 2-10); 3.57 (m, 4H, N (CH 2CH 3) 2O); 3.67,3.72 (two doublets, J=18.9Hz, 2H, CH 2-14); 5.03 (m, 1H, H-7); 5.4 (bandwidth signals, 1H, OH-7); 6.05 (s, 1H, OH-9); 7.96 (m, 2H, H-2+H-3); 8.26 (m, 2H, H-1+H-4); 13.3 (bandwidth signals, 2H, OH-6+OH-11)
The preparation of embodiment 15:4-demethoxylation-7-deoxidation-14-(N-morpholino) daunomycinone (A24)
Title compound is pressed embodiment 1, and described the latter presses J.Org.Chem. by 4-demethoxylation-7-deoxidation-14-bromo daunomycinone preparation, and 42,3653 (1977) the described methods that are used for daunomycinone are obtained by the bromination of 4-demethoxylation-7-deoxidation daunomycinone.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (96: 4, volume ratio), Rf=0.33.
FAB-MS：m/e?438[M+H] +
1H-NMR (200MHz, CDCl 3) δ: 1.9-2.0 (m, 2H CH 2-8); 2.63 (m, 4H, N (CH 2CH 2) 2O); 2.8-3.2 (m, 4H, CH 2-7+CH 2-10); 3.46,3.60 (two doublets, J=15.0Hz, 2H, CH 2-14); 3.78 (m, 4H, N (CH 2CH 2) 2O); 7.82 (m, 2H, H-2+H-3); 8.32 (m, 2H, H-1+H-4); 13.44,13.46 (two doublets, OH-6+OH-11)
The preparation of embodiment 16:7-deoxidation-14-(N-morpholino) daunomycinone (A17)
(N-morpholino) daunomycinone of jolting 14-under atmospheric Hydrogen Vapor Pressure (A1) 1.5g, 5%Pd/C 3.3mmol) (300mg) and the mixture in the 250ml dioxanes 1 hour.Filtration catalizer removes solvent under reduced pressure then, silica gel column chromatography purification residue (eluent is 96: 4 a methylene chloride of volume ratio).Isolate the title compound (0.4g, 28%) of red powder, the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate, the reuse ether sedimentation.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (96: 4, volume ratio), Rf=0.20.FAB-MS:m/e 468 [M+H] + 1H-NMR (200MHz, DMSO-d6) δ: 1.7-2.2 (m, 2H CH 2-8); 2.83 (m, 2H CH 2-7); 2.91 (m, 2H CH 2-10); 3.3,3.8 (m, 8H, morpholine hydrogen; 3.97 (s, 3H, OCH 3-4); 4.8 (m, 2H CH 2-14); 6.14 (bandwidth signals, OH-9); 7.65 (m, 1H, H-3); 7.91 (m, 2H, H-1+H-2); 10.4 (bandwidth signals, 1H, HN +); 13.34 (s, 1H, OH-11); 13.85 (s, 1H, OH-6)
The preparation of embodiment 17:13-dihydro-14-(N-morpholino) daunomycinone (A59)
Ether is closed magnesium bromide, and (2.24g, (2.10g is 4.34mmol) in the stirred suspension of oxolane (80ml) 8.68mmol) to be added drop-wise to 14-(N-morpholino) daunomycinone (A1) under argon atmospher.With sodium borohydride (0.164g, 4.34mmol) be added in batches resulting at-40 ℃ down in the refrigerative mixture.After stirring 1.5 hours under-40 ℃, drip methanol (25ml) cessation reaction.Remove volatile matter under reduced pressure, on silica gel with the column chromatography residue (eluent is that volume ratio is 94: 6 a chloroform/methanol) of purifying.Isolate the title compound of red powder, the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate, the reuse ether sedimentation.At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is chloroform/methanol (94: 6, volume ratio), Rf=0.30.FAB-MS:m/e 486[M+H] + 1H-NMR (200MHz, DMSO-d6) δ: 1.7-2.2 (m, 2H CH 2-8); 2.3-2.8 (m, 6H, CH 2-14+N (CH 2CH 2) 2O); 2.86 (m, 2H CH 2-10); 3.57 (m, 5H, N (CH 2CH 2) 2O+CH-13); 3.97 (s, 3H, OCH 3-4); 4.81 (d, J=5.5Hz, 1H, OH-13); 5.03 (m, 1H, H-7); 5.20 (m, 1H, OH-7); 5.6,5.8 (bandwidth signals 1H, OH-9); 7.5-8.0 (m, 3H, H-1+H-2+H-3); 13.3 (bandwidth signals, 1H, OH-11); 13.9 (bandwidth signals, 1H, OH-6)
The preparation of embodiment 18:7-deoxidation-13-dihydro-14-(N-morpholino) daunomycinone (A60)
With sodium dithionite (2.15g, 1.23mmol) solution in water (8ml) is added drop-wise to 13-dihydro-14-(N-morpholino) daunomycinone as preparation as described in the embodiment of front (0.240g is 0.494mmol) in the agitating solution in dimethyl formamide (16ml) under room temperature in nitrogen atmosphere.After the stirring at room 1 hour, in reactant mixture impouring water (250ml), with ethyl acetate extraction (6 * 25ml).Separate each layer, wash organic layer with water, obtain the thick product of 300mg with dried over sodium sulfate and evaporation, on silica gel with the column chromatography thick product (eluent is 96: 4 a chloroform/methanol of volume ratio) of purifying.Isolate the title product (116mg, 50%) of red powder, the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate, uses ether sedimentation then.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is chloroform/methanol (96: 4, volume ratio), Rf=0.20.FAB-MS:m/e 470[M+H] + 1H-NMR (400MHz, DMSO-d6) δ: 1.56 (m, 1H, H-8ax); 1.82 (m, 1H, H-8eq); (2.38 dd, J=7.7,12.8Hz, 1H, CH (H)-14); (2.63 dd, J=3.7,12.8Hz, 1H, CH (H)-14); 2.45 (m, 4H, N (CH 2CH 2) 2O); 2.6-2.9 (m, 4H, CH 2-10+CH 2-7); 3.53 (m, 4H, N (CH 2CH 2) 2O); 3.53 (m, 1H, CH-13); 3.94 (s, 3H, OCH 3-4); 4.65 (d, J=5.1, Hz, 1H, OH-13); 4.76 (bandwidth signals, 1H, OH-9); 7.58 (m, 1H, H-3); 7.86 (m, 2H, H-1+H-2); 13.36 (s, 1H, OH-11); 13.88 (s, 1H, OH-6);
The preparation of embodiment 19:4-demethoxylation-7-deoxidation-10-hydroxyl-14-(N-morpholino) daunomycinone (A61)
With ruthenium trichloride hydrate (27mg, 0.1mmmol) and sodium metaperiodate (0.48g, 2.2mmol) drips of solution in water (3ml) is added to by J.Org.Chem., 48,4-demethoxylation-7-the deoxidation-9 of 2820 (1983) described preparations, 10-dehydration daunomycinone (0.5g, 1.5mmol) in 1: 1 ethylacetate/acetonitrile (20ml) under the argon atmospher in the suspension of 0 ℃ of stirring.0 ℃ down stir 0.5 hour after, with in the reactant mixture impouring sodium thiosulfate solution (20ml) and use dichloromethane extraction.Separate each layer, the washing organic layer obtains the 300mg crude product with dried over sodium sulfate and evaporation, on silica gel with column chromatography this crude product (eluent is 50: 0.2 a chloroform/methanol of volume ratio) of purifying.Isolate red powder 4 demethoxylations-7-deoxidation-10-hydroxyl daunomycinone (194mg, 35%), m.p.241-242 ℃ (decomposition).
Press J.Org.Chem., 42,3653, (1977) described bromination process that is used for daunomycinone prepares 4-demethoxylation-7-deoxidation-10-hydroxyl-14-bromo daunomycinone by 4-demethoxylation-7-deoxidation-10-hydroxyl daunomycinone.Red powder; M.p.223-225 ℃ (decomposition).
According to embodiment 1 described method, 4-demethoxylation-7-deoxidation-10-hydroxyl-14-bromo daunomycinone is converted into title compound, isolate with red powder, the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate, the reuse ether sedimentation.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is chloroform/methanol (96: 4, volume ratio), Rf=0.30.FAB-MS:m/e 453[M+H] + 1H-NMR (200MHz, DMSO-d6) δ: 1.8-3.0 (m, 4H, CH 2-8+CH 2-7); 2.36 (m, 4H, N (CH 2CH 2) 2O); 3.47 (m, 4H, N (CH 2CH 2) 2O); 3.59 (s, 2H, CH 2-14); 4.90 (s, 1H, H-10); 5.60 (bandwidth signals, 1H, OH-10); 5.67 (s, 1H, H-9); 7.94 (m, 2H, H-2+H-3); 8.27 (m, 2H, H-1+H-4); 13.30 (bandwidth signals, 2H, OH-6+OH-11);
The preparation of embodiment 20:4-demethoxylation-4-hydroxyl-7-deoxidation-7-(N-morpholino) daunomycinone (A62)
Will be by Il Farmaco at Ed.Sc., described in 35,347 (1980) by 6,7,11-three carbethoxyl group daunomycinone (G1:R b=H, R c=COCH 3, Re 1=OCOOC 2H 5) preparation 4-deoxy-4-hydroxyl-O 6, O 7(1.3g 2.5mmol) is dissolved in the mixture of dichloromethane (40ml) and methanol (40ml)-diethoxy carbonyl daunomycinone, adds the 1ml morpholine.At room temperature kept mixture 20 hours.Removal of solvent under reduced pressure, the mixture of use dichloromethane and acetone (9: 1, volume ratio) makes eluent system and on silica gel, crude product is carried out the flash chromatography separation, obtain title compound, the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate (0.3g, productive rate: 25%), the reuse ether sedimentation.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (9: 1, volume ratio), Rf=0.8.FAB=MS:m/e 502[M+H] + 1H-NMR (200MHz, DMSO-d6) δ: 1.85 (m, 1H, H-8ax); 2.10 (m, 1H, OCH 2CH (Hax) N); 2.20 (m, 1H, H-8eq); (2.32 d, J=10.7Hz, 1H, CH (H)-14); 2.40 (m, 2H, NCH 2CH 2OH); 2.68 (m, 1H, OCH 2CH (Heq) N); 2.77,2.86 (d, J=19.2Hz, 1H, H-10ax); (2.83 d, J=10.7Hz, 1H, CH (H)-14); 3.07,3.10 (d, J=19.2Hz, 1H, H-10eq); 3.47 (m, 2H, NCH 2CH 2OH); 3.57 (m, 1H, NCH 2CH (Hax) O); 3.90 (m, 1H, NCH 2CH (Heq) O); 3.97 (s, 3H, OCH 3-4); 4.40 (m, 1H, CH 2OH); 5.00 (m, 1H, H-7); 5.23 (d, J=7.7Hz, 1H, OH-7); 5.32,5.34,5.84,5.93 (s, 2H, OH-9+OH-13); 7.63 (m, 1H, H-3); 7.87 (m, 2H, H-1+H-2); 13.31 (bandwidth signals, 1H, OH-11); 13.97 (bandwidth signals, 1H, OH-6)
Embodiment 21:4-demethoxylation-7, the preparation of 9-dideoxy-14-(N-morpholino) daunomycinone (A63)
Press J.Org.Chem., 42,3653 (1977) the described bromination process that are used for daunomycinone are by by Synt.Commun., 15, the 4-demethoxylation-7 of 1081 (1985) described preparations, 9-dideoxy-10 hydroxyl daunomycinone prepares 4-demethoxylation-7,9-dideoxy-14-bromine daunomycinone.
According to embodiment 1 described method, with 4-demethoxylation-7,9-dideoxy-14-bromo daunomycinone is converted into title compound, isolates with red powder, and the methanolic hydrogen chloride liquid that adds stoichiometric amount makes it be converted into corresponding hydrochlorate, the reuse ether sedimentation.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is chloroform/methanol (98: 2, volume ratio), Rf=0.23.FAB-MS:m/e 422[M+H] + 1H-NMR (200MHz, pyridine-d5) δ: 1.78 (m, 1H, H-8ax); 2.18 (m, 1H, H-8eq); 2.54 (m, 4H, N (CH 2CH 2) 2O); 2.70 (m, 1H, H-9); 2.9-3.3 (m, 4H, CH 2-10+CH 2-7); 3.43 (m, 2H CH 2-14); 3.78 (m, 4H, N (CH 2CH 2) 2O); 7.75 (m, 2H, H-2+H-3); 8.39 (m, 2H, H-1+H-4); 13.80 bandwidth signals, 2H, OH-6+OH-11)
The preparation of embodiment 22:4-demethoxylation-4-hydroxyl-14-(N-morpholino) daunomycinone (A64)
By the Yong diox 1ml bromine is diluted to the bromine solutions that 50ml obtains with 10.3ml and handles by J.Antibiotics the 4-demethoxylation of 31,178 (1978) described preparations-4-hydroxyl daunomycinone (1.4g, 3.6mmol) suspension in the 20ml diox.At room temperature stirred reaction mixture is 3 hours, adds the resulting 4-demethoxylation of 50ml petroleum ether precipitation-4-hydroxyl-14-bromo daunomycinone.Filtering-depositing with petroleum ether and vacuum drying, obtains 1.35g (80% productive rate) crude product, and it is directly used in following reaction.Handle 0.75g (1.6mmol) 4-demethoxylation-4-hydroxyl-suspension of 14-bromo daunomycinone in the 50ml dichloromethane, the mixture that stirring at room produced 24 hours with 0.28g (3.2mmol) morpholine.Removal of solvent under reduced pressure then, with dichloromethane and methanol mixture (95: 5, volume ratio) makes eluent system and on silica gel, crude product is carried out the flash chromatography separation, obtain title compound, methanolic hydrogen chloride liquid makes it be converted into corresponding hydrochlorate (0.16g when adding stoichiometric amount, productive rate 20%), reuse ether sedimentation.
At kieselgel F 254(Merck) carry out TLC on and analyze, expanding body is methylene chloride (9: 1, volume ratio), Rf=0.6.FAB-MS:m/e 470[M+H] + 1H-NMR (400MHz, DMSO-d6) δ: 2.01 (dd, J=4.7,14.1Hz, 1H, H-8ax); 2.31 (dd, J=14.1Hz, 1H, H-8eq); 2.92,3.16 (two doublets, J=18.8Hz, 2H, CH 2-10); 3.1-3-3 (m, 4H, N (CH 2CH 2) 2O); 3.7-4.0 (m, 4H, N (CH 2CH 2) 2O); 4.80,4.87 (two doublets, J=18.8Hz, 2H, CH 2-14); 5.11 (m, 1H, H-7); 5.70 (bandwidth signals, 1H, OH-7); 6.34 (s, 1H, OH-9); 7.41 (m, 1H, H-3); 7.8-7.9 (m, 2H, H-1+H-2); 10.40 (bandwidth signals, 1H, HN +); 11.98 (s, 1H, OH-4); 12.80 (s, 1H, OH-6); 13.40 (s, 1H, OH-11);
Biologic test
Measure of the self aggregation active inhibition of the anthracyclinone derivatives of formula A by using light-scattering analysis to amyloid-beta fragment 25-35 and PrP fragment 106-126.
Press Nature 362:543 such as Forloni, 1993 use mechanochemical method by synthetic β 25-35 (GSNKGAIIGLH) of 430AApplied Biosystems instrument and PrP106-126 (KTNMKHMAGAAAAGAVVGGLG), and are purified by reversed-phase HPLC (Beckman Inst.mod243).Measure the light scattering of peptide solution with fluorescence spectrophotometry (Perkin Elmer LS50B), monitor at 600nm place and excite and launch.Concentration with 0.5-1mg/ml (being respectively 0.4-0.8mM and 0.2-0.4mM) is dissolved in amyloid-beta fragment 25-35 and PrP106-126 in the 10mM phosphate buffered solution of pH5, and they were assembled in 1 hour automatically.
In the peptide solution in the time of will being dissolved in testing compound in the 5mMTris buffer of pH7.4 and being added to preparation with several concentration (0.2-2mM), to estimate the fibril forming process.Show accumulative inhibition fully with the chemical compound that in embodiment 1-22, prepares with molar concentrations addings such as amyloid-beta fragment 25-35 and PrP106-126.
Neurotoxicity:
By the period of embryo is that the cerebral cortex of 17 days tire Mus obtains neuronal cell, and as Mol.Brain.Res. such as Forloni, 16:128, and 1992 describedly cultivate in the presence of hyclone (10%).
Come the intrinsic cytotoxicity of assessing compound A to the variable concentrations chemical compound of micro-molar concentration scope by cortical neuron being exposed to repeatedly nanomole.
Quantize nerve cell death (J.Im-munol.Meth., 65,55-63,1983) with described colorimetrys such as Mossmann.
In 10 μ m concentration, all test compounds all do not have any neurotoxicity effect.

Claims (29)

1. acceptable salt is used for the treatment of purposes in the medicine of amyloidosis in preparation on the anthrone of formula A or its pharmacology:
R wherein 1Expression:
-hydrogen or hydroxyl;
-Shi OR 6Group, R wherein 6Be C 1-C 6Alkyl, C 5-C 6Cycloalkyl or CH 2Ph, phenyl ring (Ph) randomly is selected from F, Cl, Br, C by 1,2 or 3 1-C 6Alkyl, C 1-C 6Alkoxyl and CF 3Substituent group replace; Or
-Shi OSO 2R 7Group, R wherein 7Be C 1-C 6Alkyl or randomly be selected from halogen and C by 1,2 or 3 1-C 6The ph that the substituent group of alkyl replaces;
R 2Expression hydrogen, hydroxyl, OR 6, COOH or COOR 6, R wherein 6As defined above;
R 3Expression hydrogen, hydroxyl or OR as defined above 6
R 4Expression hydrogen, methyl or formula XCH 2R 8Group, wherein X is CO, CH 2, group shown in CHOH or the following formula:
Figure A9519074300022
Wherein m is 2 or 3, and R 8For
-hydrogen or hydroxyl;
-Shi NR 9R 10Group, wherein:
-R 9And R 10Be selected from independently of one another:
(a) hydrogen,
(b) randomly by hydroxyl, CN, COR 11, COOR 11, CONR 11R 12, O (CH 2) nNR 11R 12(n is 2-4) or NR 11R 12The C that replaces 1-C 6Alkyl or C 2-C 6Alkenyl, wherein R 11And R 12Be selected from hydrogen, C independently of one another 1-C 12Alkyl or C 2-C 12Alkenyl or randomly be selected from C by one or more 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the phenyl of the substituent group of CN replacement,
(c) randomly by COR 11, COOR 11Or the C of OH replacement 3-C 6Cycloalkyl, wherein R 11As defined above,
(d) randomly on phenyl ring, be selected from C by one or more 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the phenyl (C of the substituent group of CN replacement 1-C 4Alkyl or C 2-C 4Alkenyl), or
(e) COR 11, COOR 11, CONR 11R 12, CONH 2NR 11R 12, CONR 11COOR 12Or SO 2R 12, R wherein 11And R 12As defined above, or-R 9R 10Form with the nitrogen-atoms that links to each other with them:
(f) randomly by C 1-C 4Alkyl or C 1-C 4The morpholine ring that alkoxyl replaces,
(g) randomly by C 1-C 6Alkyl, C 2-C 6Alkenyl or optional be selected from C by one or more 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the piperazine ring of the phenyl replacement of the substituent group of CN replacement, or
(h) randomly by OH, NH 2, COOH, COOR 11Or CONR 11R 12(R wherein 11And R 12C as defined above), 1-C 6Alkyl, C 2-C 6Alkenyl or randomly be selected from C by one or more 1-C 6Alkyl, C 1-C 6Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or pyrrolidine ring or the piperidine ring or the tetrahydro pyridine ring of the phenyl replacement of the substituent group of CN replacement;
-Shi OR 6Or SR 6Group, R wherein 6As defined above;
The group of-Shi O-Ph, wherein benzene (Ph) ring is randomly by nitro, amino or NR as defined above 9R 10Replace;
Group shown in the-Shi B:
Figure A9519074300041
R wherein 13Expression hydrogen, COR 11(R wherein 11As defined above) or peptide residue, R 14Be halogen or formula OSO 2R 7(R wherein 7Group as defined above); Or
Group shown in-Shi C or the D:
Wherein E is formula COOR 11Or CONR 9R 10(R wherein 9, R 10And R 11Group as defined above); With
R 5Expression hydrogen, hydroxyl, formula OR 6Or NR 9R 10(R wherein 6, R 9And R 10Group as defined above), or the group shown in the formula F: R wherein 6, R 6And R 10As defined above, p is 1-6.
2. according to the purposes of claim 1, R wherein 1Be hydrogen or methoxyl group.
3. according to the purposes of claim 1 or 2, R wherein 2Be hydrogen.
4. according to the purposes of aforementioned arbitrary claim, R wherein 3Be hydroxyl.
5. according to the purposes of aforementioned arbitrary claim, R wherein 4Be formula XCH 2R 8Shown in group, wherein X is CO, CH 2Or following formula group:
Figure A9519074300051
And R 8Be hydrogen, formula NR 9R 10Group, (wherein Ph ring is randomly by NR for formula O-Ph 9R 10Replacement) group shown in, the group shown in formula B or the formula C, wherein R 9And R 10Be selected from independently of one another:
(a ') hydrogen,
(b ') is randomly by O (CH 2) nNR 11R 12Or NR 11R 12(wherein n, R 11And R 12Such as claim 1 definition) C that replaces 1-C 4Alkyl,
(d ') randomly is selected from C by one or more on phenyl ring 1-C 4Alkyl, C 1-C 4Alkoxyl, F, Br, Cl, CF 3, OH, NH 2Or the benzyl of the substituent group of CN replacement, or
(e ') COCF 3Or COCH 2NR 11R 12, wherein, R 11And R 12As defined above,
Or-R 9And R 10Form with the nitrogen-atoms that links to each other with them:
(f ') morpholine ring,
(g ') is randomly by C 1-C 4The piperazine ring that alkyl replaces, or
(h ') pyrrolidine ring or piperidine ring, or tetrahydro pyridine ring,
R in group shown in the formula B 13Be hydrogen, the R in group shown in the formula B 14Be I or OSO 2(C 1-C 4) alkyl, and the E in group shown in the formula C is formula CONR ' 9R ' 10Shown group, wherein R ' 9And R ' 10Form randomly by C with the nitrogen-atoms that links to each other with them 1-C 4The piperazine ring that alkyl replaces.
6. according to the purposes of claim 5, R wherein 4Be group shown in the following formula:
Or formula XCH 2R 8Group, wherein X is CO or CH 2, R 8Be hydrogen, formula NR 9R 10Shown in group, group shown in the formula O-Ph, wherein Ph ring is randomly by NH 2Or NHCOCH 2N (C 1-C 4Alkyl) 2Replace group, wherein R shown in formula B or the formula C 9And R 10Be selected from independently of one another:
(a ') hydrogen,
(b ' ') randomly by O (CH 2) nNH 2Or NH 2Methyl or ethyl that (wherein n is as defined above) replaces,
(d ") randomly is selected from C by 1,2 or 3 on phenyl ring 1-C 4Alkyl, C 1-C 4The benzyl that the substituent group of alkoxyl replaces, or
(e ") COCF 3Or COCH 2N (C 1-C 4Alkyl) 2,
Or-R 9And R 10Form with the nitrogen-atoms that links to each other with them:
(f ") morpholine ring,
(g ") is randomly by C 1-C 4The piperazine ring that alkyl replaces, or
(h ") pyrrolidine ring, piperidine ring, or 1,2,3,6-tetrahydro pyridine ring,
R in the group shown in the formula B 13Be hydrogen, R in the group shown in the formula B 14Be I or OSO 2(C 1-C 4Alkyl), and shown in the formula C in the group E be formula CONR ' 9R ' 10Shown in group, wherein R ' 9And R ' 10Form one randomly by C with the nitrogen-atoms that links to each other with them 1-C 4The piperazine ring that alkyl replaces.
7. according to the purposes of aforementioned arbitrary claim, R wherein 5Be hydrogen, hydroxyl or formula NR 9R 10Shown in group.
8. according to the purposes of aforementioned arbitrary claim, wherein this medicine is used for the treatment of the AL amyloidosis, Alzheimer disease or Down syndrome.
9. according to the purposes of aforementioned arbitrary claim, wherein this medicine is the unit dosage form that contains 5-500mg formula A chemical compound or its pharmaceutically acceptable salt.
10. as anthrone and the pharmaceutically acceptable salt thereof of the defined a kind of formula A of claim 1, condition is:
-work as R 1Be H, OH or OCH 3, R 2Be H, R 3Be OH and R 4Be formula XCH 2OH or XCH 3(wherein X such as claim 1 definition) shown in during group, R 5Can not be R 9And R 10As (a) to (c) in claim 1 or (e) to (h) defined NR down 9R 10
-work as R 1Be H, OH or OCH 3, R 2Be H, OH, COOCH 3And R 4Be formula XCH 3Or XCH 2During group shown in the OH (wherein X is as defined above), R 5Can not be H or OH;
-work as R 1Be H or OH, R 5And R 4Be OH, and R 2During for H, R 4Can not be R ' wherein 6Be phenyl, benzyl, C 1-C 6Alkyl or C 5-C 6The COCH of cycloalkyl 2OR ' 6
The chemical compound of-Shi A is not one of following derivant:
14-(N-morpholino) daunomycinone
14-(N-piperidino) daunomycinone
14-acetylamino daunomycinone
14-acetylaminohydroxyphenylarsonic acid 4-demethoxylation daunomycinone
14-(N-morpholino) fuchsin ketone
14-(N-methyl-N-piperazine-1-yl) daunomycinone
14-(N-morpholino) fuchsin ketone
14-(N-methyl-N-piperazine) daunomycinone.
11. according to a kind of chemical compound of claim 10, wherein R 1Be hydrogen or methoxyl group.
12. according to a kind of chemical compound of claim 10 or 11, wherein R 2Be hydrogen.
13. according to each a kind of chemical compound among the claim 10-12, wherein R 3Be hydroxyl.
14. according to each a kind of chemical compound among the claim 10-13, wherein R 4Be formula XCH 2R 8Shown in group, wherein X is CO, CH 2Or group shown in the following formula:
Figure A9519074300081
And R 8Be hydrogen, formula NR 9R 10Group, (wherein Ph ring is randomly by NR for formula O-Ph 9R 10Replacement) group shown in, the group shown in formula B or the formula C, wherein R 9And R 10Be selected from independently of one another:
(a ') hydrogen,
(b ') is randomly by O (CH 2) nNR 11R 12Or NR 11R 12(wherein n, R 11And R 12Such as claim 1 definition) C that replaces 1-C 4Alkyl,
(d ') randomly is selected from C by one or more on phenyl ring 1-C 5Alkyl, C 1-C 4Alkoxyl, F, Br, C1, CF 3, OH, NH 2Or the benzyl of the substituent group of CN replacement, or
(e ') COCF 3Or COCH 2NR 11R 12, wherein, R 11And R 12As defined above,
Or R 9R 10Form with the nitrogen-atoms that links to each other with them:
(f ') morpholine ring,
(g ') is randomly by C 1-C 4The piperazine ring that alkyl replaces, or
(h ') pyrrolidine ring or piperidine ring, or tetrahydro pyridine ring,
R in group shown in the formula B 13Be hydrogen, the R in group shown in the formula B 14Be I or OSO 2(C 1-C 4And the E in group shown in the formula C is formula CONR ' alkyl), 9R ' 10Shown group, wherein R ' 9And R ' 10Form randomly by C with the nitrogen-atoms that links to each other with them 1-C 4The piperazine ring that alkyl replaces.
15. according to a kind of chemical compound of claim 14, wherein R 4Be group shown in the following formula: Or formula XCH 2R 8Shown group, wherein X is CO or CH 2, R 8Be hydrogen, formula NR 9R 10, group shown in the formula O-Ph, wherein the Ph ring is randomly by NH 2Or NHCOCH 2N (C 1-C 4Alkyl) 2Replace group, wherein R shown in formula B or the formula C 9And R 10Be selected from independently of one another:
(a ") hydrogen,
(b ") is randomly by O (CH 2) nNH 2Or NH 2Methyl that replaces or ethyl wherein n as defined above,
(d ") randomly is selected from C by 1,2 or 3 on phenyl ring 1-C 4Alkyl and C 1-C 4The benzyl that the substituent group of alkoxyl replaces, or
(e ") COCF 3Or COCH 2N (C 1-C 4Alkyl) 2,
Or R 9And R 10Form with the nitrogen-atoms that links to each other with them:
(f ") morpholine ring,
(g ") is randomly by C 1-C 4The piperazine ring that alkyl replaces, or
(h ") pyrrolidine ring, piperidine ring or 1,2,3,6-tetrahydro pyridine ring,
R in the group shown in the formula B 13Be hydrogen, R in the group shown in the formula B 14Be I or OSO 2(C 1-C 4Alkyl), and shown in the formula C in the group E be formula CONR ' 9R 10Shown in group, wherein R ' 9And R ' 10Form one randomly by C with the nitrogen-atoms that links to each other with them 1-C 4The piperazine ring that alkyl replaces.
16. according to each a kind of chemical compound among the claim 10-15, wherein R 5Be hydrogen, hydroxyl or formula NR 9R 10Described group.
17. method for preparing as anthrone or its pharmaceutically acceptable salt of the defined formula A of claim 10, this method comprises by the described anthrone of suitable chemical improvement by known anthrone preparation formula A, with, if need, the formula A anthrone that is produced be converted into its a kind of pharmaceutically acceptable salt.
18. one kind prepares, wherein R defined as claim 10 1Be described formula OR 6Group, R 2Be hydrogen or COOCH 3, R 3Be OH, R 4Be C 1Or C 2Alkyl or COCH 3And R 5Be hydrogen, hydroxyl or OCOOC 2H 5The anthrone of formula A or the method for its pharmaceutically acceptable salt, this method comprises:
(1) 6-, the 11-of chemical compound and the 7-hydroxyl that may exist shown in the protection following formula G:
Figure A9519074300101
R wherein bExpression hydrogen or COOCH 3, R cBe C 1Or C 2Alkyl or COCH 3R eBe hydrogen or hydroxyl, thereby become derivant shown in the formula G1:
Figure A9519074300102
R wherein bAnd R cAs defined above, R ' eBe hydrogen or OCOOC 2H 5Group;
(2) make derivant demethylation shown in the formula G1 and make 4-hydroxy compounds shown in the formula G2 that is produced and formula R 6Halo derivatives suitable shown in the Hal reacts:
Figure A9519074300111
R wherein bAnd R ' eAs defined above, R 6Such as claim 1 definition, Hal is a halogen;
(3) make the 6-and the 11-phenolic hydroxyl group deblocking of the 4-O-alkyl derivative that is produced, thereby obtain chemical compound shown in the formula G3:
R wherein 6, R b, R cAnd R e' as defined above, and if desired, when R ' e is O-COOC 2H 5The time, make the 7-hydroxyl deblocking of chemical compound G3; With
(4) if need, the described formula A chemical compound that is produced is converted into its pharmaceutically acceptable salt.
19. one kind prepares, wherein R defined as claim 10 1Be aforesaid formula OSO 2R 7Shown in group, R 2Be hydroxyl or COOCH 3, R 3Be OH, R 4Be C 1Or C 2Alkyl or COCH 3And R 5Be the formula A anthrone of hydrogen or hydroxyl or the method for its pharmaceutically acceptable salt, this method comprises: use formula HalSO 2R 7Change shown in (wherein Hal is a halogen)
Figure A9519074300113
R wherein bBe hydroxyl or COOCH 3, R cBe C 1Or C 2Alkyl or COCH 3And R eBe hydrogen or hydroxyl; With, if desired, gained formula A chemical compound is converted into its pharmaceutically acceptable salt.
20. one kind prepares, wherein R defined as claim 10 3Be OH, R 4Be COCH 3And R 5Be formula NR 9R 10(R wherein 9And R 10Such as claim 1 definition, condition is R 9Or R 10Can not be for hydrogen or as the defined formula COR of claim 1 11Or COOR 11Shown in group) shown in the anthrone of formula A of group or the method for its pharmaceutically acceptable salt, this method comprises:
Make the glycoside unit and formula NHR of formula K 9R 10(R 9And R 10The reaction of amine as defined above):
Figure A9519074300121
R wherein 1And R 2Such as claim 10 definition; With, if desired, the described formula A chemical compound that is produced is converted into its pharmaceutically acceptable salt.
21. one kind prepare as claim 10 defined, R wherein 3Be OH, R 4Be COCH 3And R 5Be formula NR 9R 10(R wherein 9And R 10Such as claim 1 definition, condition is R 9And R 10In one of be hydrogen atom, another is not a hydrogen or as the defined formula COR of claim 1 11Or COOR 11Shown in group) shown in the anthrone of formula A of group or the method for its pharmaceutically acceptable salt, this method comprises:
(1) the glycoside unit with above-mentioned formula K protects the 13-ethylenedioxy derivant that becomes formula K1:
Figure A9519074300131
R wherein 1And R 2Such as claim 10 definition;
(2) make above-mentioned formula K1 derivant and formula NHR 9R 10(R 9And R 10) as defined above) and shown in amine reaction;
(3) make the amino derivant 13-carbonyl deblocking that replaces of 7-of the formula K2 that is produced:
R wherein 1, R 2, R 9And R 10As defined above; (4) if desired, described formula A chemical compound is changed into its pharmaceutically acceptable salt.
22. one kind prepares, wherein R defined as claim 10 3Be OH, R 4Be COCH 3And R 5Be formula NH 2The anthrone of A or the method for its pharmaceutically acceptable salt, this method comprises:
(1) with a kind of oxidizer treatment such as the defined formula K2 derivant of claim 21, wherein NR 9R 10Expression 3 ', 4 '-dimethoxy benzyl amino;
(2) make the 13-carbonyl deblocking of the 7-amino-substituted compounds of the formula K3 that is produced:
R wherein 1And R 2Such as claim 10 definition; With
(3) if need, can make the described formula A chemical compound that is produced be converted into its pharmaceutically acceptable salt.
23 1 kinds prepare as claim 10 defined, R wherein 3Be OH or H, R 4Be COCH 2NR 9R 10(R wherein 9And R 10Such as claim 1 definition, condition is that they can not be formula COR 11Or COOR 11Shown group) and R 5Be the anthrone of the formula A of hydrogen or OH or the method for its pharmaceutically acceptable salt, this method comprises:
(1) incites somebody to action wherein R 1, R 2And R 3Such as claim 10 definition and R eFor the formula L chemical compound of hydrogen or hydroxyl is converted into wherein R 1, R 2, R 3And R eThe 14-bromo derivative of corresponding formula L1 as defined above;
Figure A9519074300141
(2) make 14-bromo derivative and the formula NHR of formula L1 9R 10Shown amine reaction, wherein R 9And R 10As defined above; With
(3) if need, the described formula A chemical compound that is produced is changed into its pharmaceutically acceptable salt.
24. one kind prepares, wherein R defined as claim 10 3Be OH, R 4Be formula COCH 2(wherein benzene (Ph) ring is randomly by nitro, amino or NR for O-Ph 9R 10(R wherein 9And R 10Such as claim 1 definition) replace) and shown in group, and R 5Be the anthrone of the formula A of hydrogen or hydroxyl or the method for its pharmaceutically acceptable salt, this method comprises:
(1) makes as the defined formula L1 chemical compound of claim 23 and a kind of randomly substituted as mentioned above phenol reactant; With
(2) if need, the described formula A chemical compound that is produced is changed into its pharmaceutically acceptable salt.
25. one kind prepares, wherein R defined as claim 10 4Be formula XCH 2R 8(R wherein 8Be group shown in formula C and the D) shown in the anthrone of formula A of group or the method for its pharmaceutically acceptable salt, this method comprises:
(1) make at 9 bit strips derivatives reaction shown in the anthrone of hydroxylating side chain and formula C ' or the D ' arranged:
(2) if need the resulting ester derivant of hydrolysis; With
(3) if need, the described formula A chemical compound that is produced is converted into its pharmaceutically acceptable salt.
26. one kind prepares, wherein R defined as claim 10 4Be formula CH 2CH 2R 8(R wherein 8Such as claim 1 definition) shown in the anthrone of formula A of group or the method for its pharmaceutically acceptable salt, this method comprises:
(1) will be as the defined wherein R of claim 10 4Be formula COCH 2R 8(R wherein 8The formula A chemical compound of group as defined above) is converted into corresponding 13-hydazone derivative;
(2), use Reducing agent to reduce above-mentioned hydazone derivative can freeze mode under the condition of quinone system character of A chemical compound; With
(3) if need, with the wherein R that is produced 4Be described CH 2CH 2R 8The described formula A chemical compound of group is converted into its pharmaceutically acceptable salt.
27. a pharmaceutical composition, it comprises as the anthrone of the defined a kind of formula A of claim 10 or its pharmaceutically acceptable salt makes active component, and is mixed with a kind of pharmaceutically acceptable carrier or diluent.
28. anthrone or its pharmaceutically acceptable salt that is used for the treatment of amyloidosis as the defined formula A of claim 10.
29. the purposes of anthrone in the amyloidosis treatment as the defined a kind of formula A of claim 1.
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CN110548023A (en) * 2019-09-19 2019-12-10 天津科技大学 Application of cochineal acid in preparation of medicines for inhibiting beta-amyloid protein aggregation

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CN110548023A (en) * 2019-09-19 2019-12-10 天津科技大学 Application of cochineal acid in preparation of medicines for inhibiting beta-amyloid protein aggregation

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